Beta-secretase modulators and methods of use

ABSTRACT

The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer&#39;s disease (AD) and related conditions. In one embodiment, the compounds have a general Formula I 
                         
wherein A, B, R 3 , R 4 , R 5 , i and j are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, methods of use for these compounds, including treatment of AD and related diseases, by administering the compound(s) of Formula I, or compositions including them, to a subject. The invention also comprises further embodiments of Formulas II and III, intermediates and processes useful for the preparation of compounds of the invention.

This application is a divisional patent application of and claimspriority to U.S. patent application Ser. No. 11/600,264, filed Nov. 14,2006, which in turn claims priority to U.S. Provisional PatentApplication No. 60/738,767, filed Nov. 21, 2005, both specifications ofwhich are hereby incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The invention relates generally to the field of pharmaceutical agentsand, more specifically, to pharmaceutically active compounds,pharmaceutical compositions and methods of use thereof, to treatBeta-Secretase mediated disorders, including Alzheimer's disease andplaque formation related conditions. The invention also relates tointermediates and processes useful in the preparation of such compounds.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a disease that affects greater than 12million aging people worldwide. AD accounts for the majority of dementiaclinically diagnosed after the age of 60. AD is generally characterizedby the progressive decline of memory, reasoning, judgement andorientation. As the disease progresses, motor, sensory, and vocalabilities are affected until there is global impairment of multiplecognitive functions. The loss of cognitive function occurs gradually,typically leading to a diminished cognition of self, family and friends.Patients with severe cognitive impairment and/or diagnosed as end-stageAD are generally bedridden, incontinent, and dependent on custodialcare. The AD patient eventually dies in about nine to ten years, onaverage, after initial diagnosis. Due to the incapacitating, generallyhumiliating and ultimately fatal effects of AD, there is a need toeffectively treat AD upon diagnosis.

AD is caused by two major physiological factors in the brain. The firstfactor, beta amyloid plaque formation, supports the “amyloid cascadehypothesis” which alleges that AD is caused by the formation ofcharacteristic beta amyloid deposits (commonly referred to as betaamyloid “plaques” or “plaque deposits”) in the brain and in cerebralblood vessels (beta amyloid angiopathy). The second factor causing AD isintraneuronal tangles, consisting of an aggregate form of the proteintau. Amyloid plaques are thought to be specific for AD, whileintraneuronal tangles are also found in other dementia-inducingdisorders. Joachim et al., Alz. Dis. Assoc. Dis., 6:7-34 (1992).

Several lines of evidence indicate that progressive cerebral depositionof beta-amyloid peptide (A-beta) plays a seminal role in thepathogenisis of AD and can precede cognitive symptoms by years or evendecades. Selkoe, Neuron 6:487 (1991). Release of A-beta from neuronalcells grown in culture and the presence of A-beta in cerebrospinal fluid(CSF) of both normal individuals and AD patients has been demonstrated.Seubert et al., Nature, 359:325-327 (1992). Autopsies of AD patientshave revealed large numbers of lesions comprising these 2 factors inareas of the human brain believed to be important for memory andcognition.

Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloid containing plaques and vascular amyloid angiopathywere also found in the brains of individuals with Down's Syndrome,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type(HCHWA-D), and other neurodegenerative disorders.

It has been hypothesized that A-Beta formation is a causative precursoror factor in the development of AD. Deposition of A-beta in areas of thebrain responsible for cognitive factors is a major factor in thedevelopment of AD. Beta amyloid plaques are primarily composed ofamyloid beta peptide (A-beta). A-Beta peptide is derived from theproteolytic cleavage of a large transmembrane amyloid precursor protein(APP), and is a peptide ranging in about 39-42 amino acids. A-Beta 42(42 amino acids long) is thought to be the major component of theseplaque deposits. Citron, Trends in Pharmacological Sciences, 25(2):92-97(2004).

Several aspartyl proteases are thought to be involved in the processingor cleavage of APP, resulting in the formation of A-beta peptide. Betasecretase (BACE, also commonly referred to as memapsin) is thought tofirst cleave APP to generate two fragments of the A-beta peptide: (1) afirst N-terminus fragment and (2) a second C-99 fragment, which issubsequently cleaved by gamma secretase to generate the C-terminusfragment of the A-beta peptide. APP has also found to be cleaved byalpha-secretase to produce alpha-sAPP, a secreted form of APP that doesnot result in beta-amyloid plaque formation. This alternate pathwayprecludes the formation of A-beta peptide. A description of theproteolytic processing fragments of APP is found, for example, in U.S.Pat. Nos. 5,441,870, 5,712,130 and 5,942,400.

BACE is an aspartyl protease enzyme comprising 501 amino acids andresponsible for processing APP at the beta-secretase specific cleavagesite. BACE is present in two forms, BACE 1 and BACE 2, designated assuch depending upon the specific cleavage site of APP. Beta secretase isdescribed in Sinha et al., Nature, 402:537-554 (1999) (p 510) and PCTapplication WO 2000/17369. It has been proposed that A-beta peptideaccumulates as a result of APP processing by BACE. Moreover, in vivoprocessing of APP at the beta secretase cleavage site is thought to be arate-limiting step in A-beta production. Sabbagh, M. et al., Alz. Dis.Rev. 3:1-19 (1997). Thus, inhibition of the BACE enzyme activity isdesirable for the treatment of AD.

Studies have shown that the inhibition of BACE may be linked to thetreatment of AD. BACE 1 knockout mice fail to produce A-beta, andpresent a normal phenotype. When crossed with transgenic mice that overexpress APP, the progeny show reduced amounts of A-beta in brainextracts as compares with control animals (Luo et al., NatureNeuroscience, 4:231-232 (2001)). This evidence further supports theconcept that inhibition of beta secretase activity and a correspondingreduction of A-beta in the brain should provide a therapeutic method fortreating AD and other beta amyloid or plaque related disorders.

Several approaches have been taken to treat AD and plaque-relateddisorders. One approach has been to reduce the formation of plaque onthe brain. Particularly, a common approach has been to inhibit theactivity of beta secretase. For example, each of the following PCTpublications: WO 03/045913, WO 04/043916, WO 03/002122, WO 03/006021, WO03/002518, WO 04/024081, WO 03/040096, WO 04/050619, WO 04/080376, WO04/099376, WO 05/004802, WO 04/080459, WO 04/062625, WO 04/042910, WO05/004803, WO 05/005374, WO 03/106405, WO 03/062209, WO 03/030886, WO02/002505, WO 01/070671, WO 03/057721, WO 03/006013, WO 03/037325, Wo04/094384, Wo 04/094413, WO 03/006423, WO 03/050073, WO 03/029169 and WO04/000821, describe inhibitors of beta secretase, useful for treating ADand other beta-secretase mediated disorders.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful for themodulation of beta secretase and, to that end, useful for the regulationor reduction of the formation of A-beta peptide and consequently, thereduction of beta amyloid plaque formation on the brain. Accordingly,the compounds of the invention are useful for the treatment of AD andother beta secretase mediated disorders.

The compounds provided by the invention, including stereoisomers,tautomers, solvates, pharmaceutically acceptable salts, derivatives orprodrugs thereof, are defined by general Formula I

wherein A, B, R³, R⁴, R⁵, i and j are as described below. The inventionalso provides procedures for making compounds of Formula I, as well asintermediates useful in such procedures.

The compounds provided by the invention are capable of modulating betasecretase. To this end, the invention further provides for the use ofthese compounds for therapeutic, prophylactic, acute and/or chronictreatment of beta secretase mediated diseases, such as those describedherein. For example, the compounds are useful for the prophylaxis andtreatment of AD and other diseases or conditions involving amyloidplaque formation on the brain.

The invention also provides pharmaceutical compositions, which compriseone or more compounds of the invention, methods for the treatment ofbeta secretase mediated diseases, such as AD, using the compounds andcompositions of the invention, and intermediates and processes usefulfor the preparation of the compounds of the invention. The inventionalso provides the preparation of a pharmaceutical composition or of amedicament, containing one or more of the compounds, useful toattenuate, alleviate, or treat disorders through inhibition of betasecretase. For example, and in one embodiment, the invention provides apharmaceutical composition comprising an effective dosage amount of acompound of Formula I in association with at least one pharmaceuticallyacceptable carrier.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents and other publications recited herein are herebyincorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, the compounds, includingstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, are defined by

wherein

A is R¹—C(═O)—, R¹—OC(═O)—, R¹—NHC(═O)—, R¹—S(═O)_(b)— orR¹—NHS(═O)_(b)—, wherein

-   -   b is 1 or 2; and    -   R¹ is a partially or fully saturated 3-8 membered monocyclic,        6-12 membered bicyclic, or 7-14 membered tricyclic ring system,        said ring system formed of carbon atoms and optionally including        1-3 heteroatoms if mono cyclic, 1-6 heteroatoms if bicyclic, or        1-9 heteroatoms if tricyclic, said heteroatoms selected from O,        N, or S, wherein said ring system is optionally substituted        independently with one or more substituents of oxo, R⁷, R⁸, R⁹,        NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷,        C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷,        NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷,        C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸,        NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷,        NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;

B is R²—(CR^(2a)R^(2a))_(h)—, R²-—O—(CR^(2a)R^(2s))_(h)—,R²—S—(CR^(2a)R^(2a))_(h)— or R²—NR^(2a)—(CR^(2a)R^(2a))_(h)—, wherein

-   -   R² is C₁-C₁₀ alkyl, C₁-C₁₀ haloalkyl, C₁-C₁₀ alkenyl, C₁-C₁₀        alkynyl or a partially or fully saturated or unsaturated 3-8        membered monocyclic, 6-12 membered bicyclic, or 7-14 membered        tricyclic ring system, said ring system formed of carbon atoms        optionally including 1-3 heteroatoms if monocyclic, 1-6        heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said        heteroatoms selected from O, N, or S, wherein said C₁-C₁₀ alkyl,        C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl is optionally substituted        independently with one or more substituents of R⁹, and said ring        system is optionally substituted independently with one or more        substituents of oxo, R⁷, R⁸, R⁹, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸,        SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)NR⁷R⁷,        C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷,        NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸,        NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸,        S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸,        NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;    -   each R^(2a), independently, is H, OH, NO₂, CN, NH₂, C₁-C₁₀        alkyl, C₁-C₁₀ alkoxyl or haloalkyl; and    -   h is 0, 1, 2 or 3;

i is 1, 2 or 3;

j is 0, 1 or 2;

each R³, independently, is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R⁸ or R⁹;

R⁴ is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of R⁸ or R⁹;

R⁵ is

wherein X¹ is C(═O), O, S or NR¹²;

-   -   each X², independently, is CR¹²R¹²;    -   each of Y¹, Y² and Y³, independently, is CR¹²R¹², O, S or NR¹²;    -   m is 0, 1 or 2; and    -   o is 0, 1, 2, 3, 4 or 5;    -   provided that (a) no more than two of Y¹, Y² and Y³ is O, S or        NR¹² and (b) when    -   o is 0, then each of Y¹ and Y² is CR¹²R¹²;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with 1-5 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹,C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁸, C(O)NR⁸R⁹, C(O)NR⁹R⁹,NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹;

R⁸ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

R¹¹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

alternatively, R¹⁰ and R¹¹ taken together with the carbon or nitrogenatoms to which they are attached form a partially or fully saturated orunsaturated 5-6 membered second ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, the second ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁵ and optionally fused to a 4-7 membered third ring, the thirdring formed of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁵;

R¹² is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl, phenyl or R¹⁴;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is a saturated or partially or fully unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R¹⁵; and

R¹⁵ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, oxo, acetyl, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl or a partially or fully saturatedor unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, and optionally substitutedindependently with 1-5 substituents of halo, haloalkyl, CN, NO₂, NH₂,OH, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl or phenyl.

In another embodiment, the compounds of Formula I include R¹—C(═O)— asA, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R¹—OC(═O)— asA, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R¹—NHC(═O)— asA, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R¹—S(═O)_(b)—as A wherein b is 0, 1 or 2, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I include orR¹—NHS(═O)_(b)— as A wherein b is 0, 1 or 2, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formula I include as R¹

wherein

D¹ is CR^(1a′)R^(1a′), NR^(1a′), O or S;

D² is NR^(1a′), O or S;

E is O or S;

each R^(1a), independently, is R⁷, R⁸, R⁹, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷,C(S)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂R⁸, or S(O)₂NR⁷R⁸,provided that R^(1a) is not H;

each R^(1a′), independently, is R⁷, R⁸, R⁹, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷,C(S)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂R⁸, or S(O)₂NR⁷R⁸; and

each R^(1b), R^(1c) and R^(1d), independently, is R⁷, R⁸, R⁹, NR⁷R⁷,NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, COOR⁷, C(O)R⁸, COOR⁸, C(O)NR⁷R⁷,C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷),OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸,NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷,NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸, inconjunction with any of the above or below embodiments.

The phrase “provided that R^(1a) is not H” is intended to mean that theR¹ group (ring) may not be fully unsaturated, such as by tautomerizationof the proton, where R^(1a) was H. The present invention excludescompounds where R¹ is fully unsaturated or aromatic.

In the immediately preceeding embodiment, the compounds of Formula Iinclude R⁷, R⁸ or R⁹, independently, as each of R^(1a), R^(1b), R^(1c)and R^(1d), independently, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include as R¹

wherein

D¹ is CR^(1a′)R^(1a′), NR^(1a′), O or S;

D² is NR^(1a′), O or S;

E is O or S;

each R^(1a), independently, is R⁷, R⁸, R⁹, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷,C(S)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂R⁸, or S(O)₂NR⁷R⁸,provided that R^(1a) is not H;

each R^(1a′), independently, is R⁷, R⁸, R⁹, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷,C(S)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂R⁸, or S(O)₂NR⁷R⁸;

each R^(1b), R^(1c) and R^(1d), independently, is R⁷, R⁸, R⁹, NR⁷R⁷,NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, COOR⁷, C(O)R⁸, COOR⁸, C(O)NR⁷R⁷,C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷),OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸,NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷,NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸; and

Z¹ is a partially or fully saturated or unsaturated 5-8 memberedmonocyclic ring, said ring formed of carbon atoms optionally including1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S andoptionally substituted independently with one or more substituents ofoxo, R⁷, R⁸, R⁹, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷,COOR⁷, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷,NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷,C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸,NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸,S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂, in conjunction with any of theabove or below embodiments.

In the immediately preceeding embodiment, the compounds of Formula Iinclude R⁷, R⁸ or R⁹, independently, as each of R^(1a), R^(1b), R^(1c)and R^(1d), in conjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I include anoptionally substituted phenyl, pyridine, pyrimidine, triazine,pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiophene,thiazole, thiadiazole, isothiazole, furan, oxazole, oxadiazole orisoxazole ring as Z¹, in conjunction with any of the above or belowembodiments.

In the preceeding embodiment, the compounds of Formula I include anoptionally substituted pyrrole, imidazole, pyrazole, triazole,thiophene, thiazole, thiadiazole, isothiazole, furan, oxazole,oxadiazole or isoxazole ring as Z¹, in conjunction with any of the aboveor below embodiments.

In another embodiment, the compounds of Formula I include as R¹

wherein R^(1a) is R⁷, R⁸, R⁹, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷,C(O)NR⁷R⁸, C(S)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂R⁸, or S(O)₂NR⁷R⁸, provided thatprovided that R^(1a) is not H;

each R^(1b), R^(1c) and R^(1d), independently, is R⁷, R⁸, R⁹, NR⁷R⁷,NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, COOR⁷, C(O)R⁸, COOR⁸, C(O)NR⁷R⁷,C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷),OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸,NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷,NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸; and

k is 0, 1, 2 or 3, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includeR²—(CR^(2a)R^(2a))_(h)— as B wherein each R^(2a), independently, is H,OH, NO₂, CN, NH₂, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyl or haloalkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includeR²—O—(CR^(2a)R^(2a))_(h)— as B wherein each R^(2a), independently, is H,OH, NO₂, CN, NH₂, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyl or haloalkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includeR²—S—(CR^(2a)R^(2a))_(h)— as B wherein each R^(2a), independently, is H,OH, NO₂, CN, NH₂, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyl or haloalkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R²—NR^(2a)—(CR^(2a)R^(2a))_(h)— as B wherein each R^(2a), independently, isH, OH, NO₂, CN, NH₂, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyl or haloalkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includeR²—(CHR^(2a))_(h)— as B wherein R^(2a) is OH, NO₂, CN, NH₂, C₁-C₁₀alkyl, C₁-C₁₀ alkoxyl or haloalkyl, in conjunction with any of the aboveor below embodiments.

In another embodiment, the compounds of Formula I include R²—(CH₂)_(h)—as B, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includeR²—O—(CH₂)_(h)— as B, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includeR²—S—(CH₂)_(h)— as B, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includeR²—NH—(CH₂)_(h)— as B, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include an optionallysubstituted ring system selected from phenyl, naphthyl, pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl as R², inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include an optionallysubstituted ring system selected from phenyl, naphthyl, pyridyl,pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl and benzimidazoly as R², inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include C₁-C₁₀ alkyl,C₁-C₁₀ alkenyl or C₁-C₁₀ alkynyl as R², in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I include C₁-C₁₀haloalkyl as R², in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include H, haloalkyl,CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl as R³, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H as R³, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include C₁₋₁₀-alkyl asR³, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, haloalkyl,CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl as R⁴, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H as R⁴, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include haloalkyl orC₁₋₁₀-alkyl as R⁴, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include h as 0, 1 or2, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include h as 1, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include i as 1, 2 or3, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include i as 1, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include j as 0, 1 or2, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include j as 0, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include as R⁵

wherein

m, o, R¹², X¹, X², Y¹, Y² and Y³ are as defined herein above withrespect to compounds of formula I;

Z² is an optionally substituted, partially saturated or fullyunsaturated 5-8 membered monocyclic ring, said ring formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S, provided that (a) no more than twoof Y¹, Y² and Y³ is O, S or NR¹² and (b) when o is 0, then each of Y¹and Y² is CR¹²R¹²; and

p is 0, 1, 2, 3, 4 or 5, in conjunction with any of the above or belowembodiments.

In the immediately preceeding embodiment, the compounds of Formula Iinclude CR¹²R¹² as X¹, in conjunction with any of the above or belowembodiments.

In the preceeding embodiment, the compounds of Formula I include CHR¹²as X¹, in conjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I include CH₂ asX¹, in conjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I include C(═O)as X¹, in conjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I include 0 asX¹, in conjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I include S asX¹, in conjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I include NR¹² asX¹, in conjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I include NH asX¹, in conjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I include CR¹²R¹²as each X², independently, in conjunction with any of the above or belowembodiments.

In the preceeding embodiment, the compounds of Formula I include CHR¹²as each X², independently, in conjunction with any of the above or belowembodiments.

In the preceeding embodiment, the compounds of Formula I include CH₂ aseach X², independently, in conjunction with any of the above or belowembodiments.

In the preceeding embodiment, the compounds of Formula I include CR¹²R¹²as each of Y¹, Y² and Y³, independently, in conjunction with any of theabove or below embodiments.

In the preceeding embodiment, the compounds of Formula I include CHR¹²as each of Y¹, Y² and Y³, independently, in conjunction with any of theabove or below embodiments.

In the preceeding embodiment, the compounds of Formula I include CH₂ aseach of Y¹, Y² and Y³, independently, in conjunction with any of theabove or below embodiments.

In the preceeding embodiment, the compounds of Formula I include 0 asany one or two of Y¹, Y² and Y³, independently, in conjunction with anyof the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I include S asany one or two of Y¹, Y² and Y³, independently, in conjunction with anyof the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I include NR¹² asany one or two of Y¹, Y² and Y³, independently, in conjunction with anyof the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I include 0 as Y²and CH₂ as each of Y¹ and Y³, in conjunction with any of the above orbelow embodiments.

In the preceeding embodiment, the compounds of Formula I include S as Y²and CH₂ as each of Y¹ and Y³, in conjunction with any of the above orbelow embodiments.

In the preceeding embodiment, the compounds of Formula I include NR¹² asY² and CH₂ as each of Y¹ and Y³, in conjunction with any of the above orbelow embodiments.

In the preceeding embodiment, the compounds of Formula I include anoptionally substituted benzene, pyridine, pyrimidine, triazine,pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiophene,thiazole, thiadiazole, isothiazole, furan, oxazole, oxadiazole orisoxazole ring as Z², in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R⁵ is

wherein m, o, X¹, X², Y¹, Y² and Y³ are as defined herein with respectto compounds of formula I,

-   -   Z² is an optionally substituted phenyl, pyridine, pyrimidine,        triazine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole,        triazole, thiophene, thiazole, thiadiazole, isothiazole, furan,        oxazole, oxadiazole or isoxazole ring, each p, independently, is        0, 1, 2, 3, 4 or 5, and

R¹², in each instance, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl, benzyl, phenyl or R¹⁴, in conjunction with any of theabove or below embodiments.

In another embodiment, the invention provides compounds of Formula I,wherein

h is 1 or 2;

i is 1;

j is 0;

R¹ is

wherein R^(1a) is R⁷, R⁸, R⁹, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷,C(O)NR⁷R⁸, C(S)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂R⁸, or S(O)₂NR⁷R⁸, provided thatR^(1a) is not H;

-   -   each R^(1a′), independently, is R⁷, R⁸, R⁹, C(O)R⁷, C(O)R⁸,        C(O)NR⁷R⁷, C(S)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂R⁸,        or S(O)₂NR⁷R⁸;    -   each R^(1b), R^(1c) and R^(1d), independently, is R⁷, R⁸, R⁹,        NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, COOR⁷, C(O)R⁸, COOR⁸,        C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷,        NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸,        NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸),        OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸,        S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;    -   Z¹ is an optionally substituted phenyl, pyridine, pyrimidine,        triazine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole,        triazole, thiophene, thiazole, thiadiazole, isothiazole, furan,        oxazole, oxadiazole or isoxazole ring; and    -   k is 0, 1, 2 or 3;

R² is an optionally substituted ring system selected from phenyl,naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl andbenzimidazolyl;

each R³, independently, is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenylor C₂₋₁₀-alkynyl;

R⁴ is H, CN or C₁₋₁₀-alkyl;

R⁵ is

wherein m, o, R¹², X², Y¹, Y² and Y³ are as defined herein above;

-   -   X¹ is C(═O), O, S or NR¹²;    -   Z² is an optionally substituted phenyl, pyridine, pyrimidine,        triazine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole,        triazole, thiophene, thiazole, thiadiazole, isothiazole, furan,        oxazole, oxadiazole or isoxazole ring; and    -   p is 0, 1, 2, 3, 4 or 5.

R⁷ is H, C₁₋₁₀-alkyl or C₂₋₁₀-alkenyl, each of the C₁₋₁₀-alkyl, orC₂₋₁₀-alkenyl optionally substituted with 1-3 substituents of R⁹;

R⁸ is a ring system selected from phenyl, pyridyl, pyrimidinyl,triazinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl,benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl,isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl,isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl,1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl,cyclohexyl and cycloheptyl, said ring system optionally substitutedindependently with 1-3 substituents of R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-5 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl, or a ring system selected from phenyl, pyridyl,pyrimidinyl, triazinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl,pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl,isothiazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl and cycloheptyl, whereineach of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,tert-butyl, cyclobutyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl, benzyl or phenyl; and

R¹² is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl.

In another embodiment, the invention provides compounds generallydefined by Formula II,

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein

W is —C(═O)—, —OC(═O)—, —NHC(═O)—, —S(═O)_(b)— or —NHS(═O)_(b)—, whereinb is 1 or 2;

R¹ is

-   -   wherein R^(1a) is R⁷, R⁸, R⁹, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷,        C(S)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂R⁸, or        S(O)₂NR⁷R⁸, provided that R^(1a) is not H;    -   each R^(1b), R^(1c) and R^(1d), independently, is R⁷, R⁸, R⁹,        NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, COOR⁷, C(O)R⁸, COOR⁸,        C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷,        NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸,        NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸),        OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸,        S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;    -   Z¹ is a phenyl, pyridine, pyrimidine, triazine, pyridazine,        pyrazine, pyrrole, imidazole, pyrazole, triazole, thiophene,        thiazole, thiadiazole, isothiazole, furan, oxazole, oxadiazole        or isoxazole ring; and    -   k is 0, 1, 2 or 3;

V is —(CR^(2a)R^(2a))_(h)—, —O—(CR^(2a)R^(2a))_(h)—,—S—(CR^(2a)R^(2a))_(h)— or —NR^(2a)—(CR^(2a)R^(2a))_(h)—, wherein eachR^(2a), independently, is H, C₁-C₁₀ alkyl or haloalkyl, and h is 0, 1 or2;

R² is a C₁-C₁₀ haloalkyl or a partially or fully saturated orunsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein said ring system is optionally substitutedindependently with one or more substituents of oxo, R⁷, R⁸, R⁹, NR⁷R⁷,NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)R⁸, OC(O)R⁸,COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷,NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸,NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸,S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸,NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;

R³ is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl;

R⁴ is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of R⁸ or R⁹;

R⁵ is

-   -   wherein X¹ is C(═O), O, S or NR¹²;    -   each X², independently, is CR¹²R¹²; and    -   m is 0, 1 or 2;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with 1-5 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹,C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁸, C(O)NR⁸R⁹, C(O)NR⁹R⁹,NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹;

R⁸ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

R¹¹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

alternatively, R¹⁰ and R¹¹ taken together with the carbon atoms to whichthey are attached form a partially or fully saturated or unsaturated 5-6membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and the ring optionally substitutedindependently with 1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁵;

R¹² is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is a saturated or partially or fully unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R¹⁵;

R¹⁵ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, oxo, acetyl, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, cyclobutyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl, benzyl, phenyl or a partially orfully saturated or unsaturated 3-8 membered monocyclic or 6-12 memberedbicyclic ring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, and optionally substitutedindependently with 1-5 substituents of halo, haloalkyl, CN, NO₂, NH₂,OH, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl,isobutoxyl, tert-butoxyl, isobutyl, tert-butyl, cyclobutyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl, benzyl orphenyl;

each R¹⁶, independently, is haloalkyl, methyl, methoxyl, ethyl, ethoxyl,alkoxy-alkyl, alkylamino-alkyl, dialkylamino-alkyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, butyl, isobutyl, sec-butyl ortert-butyl;

h is 0, 1 or 2;

i is 1, 2 or 3; and

j is 0, 1 or 2.

In another embodiment, the compounds of Formula II include O as X¹, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II include C(═O) as X¹,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II include S as X¹, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II include NR¹² as X¹,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II include methyl,ethyl, propyl, isopropyl, butyl, isobutyl or sec-butyl as R¹⁶,independently, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein A is R¹—C(═O)—, R¹—OC(═O)—, R¹—NHC(═O)—, R¹—S(═O)_(b)— orR¹—NHS(═O)_(b)—, wherein

-   -   b is 1 or 2; and    -   R¹ is a partially or fully saturated 3-8 membered monocyclic,        6-12 membered bicyclic, or 7-14 membered tricyclic ring system,        said ring system formed of carbon atoms and optionally including        1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or        1-9 heteroatoms if tricyclic, said heteroatoms selected from O,        N, or S, wherein said ring system is optionally substituted        independently with one or more substituents of oxo, R⁷, R⁸, R⁹,        NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷,        C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷,        NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷,        C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸,        NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷,        NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;

B is R²—O—(CR^(2a)R^(2a))_(h)—, R²—S—(CR^(2a)R^(2a))_(h)— orR²—N(R^(2a))—(CR^(2a)R^(2a))_(h)—, wherein

-   -   R² is C₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl or a        partially or fully saturated or unsaturated 3-8 membered        monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic        ring system, said ring system formed of carbon atoms optionally        including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if        bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms        selected from O, N, or S, wherein said C₁-C₁₀ alkyl, C₁-C₁₀        alkenyl, C₁-C₁₀ alkynyl is optionally substituted independently        with one or more substituents of R⁹, and said ring system is        optionally substituted independently with one or more        substituents of oxo, R⁷, R⁸, R⁹, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸,        SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)NR⁷R⁷,        C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷,        NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸,        NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸,        S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸,        NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;    -   each R^(2a), independently, is H, OH, NO₂, CN, NH₂, C₁-C₁₀        alkyl, C₁-C₁₀ alkoxyl or haloalkyl; and    -   h is 0, 1 or 2;

i is 1, 2 or 3;

j is 0, 1 or 2;

each R³, independently, is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R⁸ or R⁹;

R⁴ is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of R⁸ or R⁹;

R⁵ is

wherein X¹ is C(═O), O, S or NR¹²;

-   -   each X², independently, is CR¹²R¹²;    -   each of Y¹, Y² and Y³, independently, is CR¹²R¹², O, S or NR¹²;    -   m is 0, 1 or 2; and    -   o is 0, 1, 2, 3, 4 or 5;    -   provided that (a) no more than two of Y¹, Y² and Y³ is O, S or        NR¹² and (b) when    -   o is 0, then each of Y¹ and Y² is CR¹²R¹²;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with 1-5 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹,C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁸, C(O)NR⁸R⁹, C(O)NR⁹R⁹,NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹;

R⁸ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

R¹¹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

alternatively, R¹⁰ and R¹¹ taken together with the carbon or nitrogenatoms to which they are attached form a partially or fully saturated orunsaturated 5-6 membered second ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, the second ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁵ and optionally fused to a 4-7 membered third ring, the thirdring formed of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁵;

R¹² is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl, phenyl or R¹⁴;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴, SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵,

R¹⁴ is a saturated or partially or fully unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R¹⁵;

R¹⁵ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, oxo, acetyl, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl or a partially or fully saturatedor unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, and optionally substitutedindependently with 1-5 substituents of halo, haloalkyl, CN, NO₂, NH₂,OH, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl or phenyl;and

each R¹⁶, independently, is haloalkyl, methyl, methoxyl, ethyl, ethoxyl,alkoxy-alkyl, alkylamino-alkyl, dialkylamino-alkyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, butyl, isobutyl, sec-butyl ortert-butyl, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II include eachindependent embodiment, as described herein for variables A, B, R¹,R^(1a), R^(1b), R^(1c), R^(1d), R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R¹⁵, W, V, X¹, X², Y¹, Y², Y³, Z¹ and Z² forcompounds of Formula I, independently, in conjunction with any of theabove or below embodiments for compounds of Formula II.

In yet another embodiment, the invention provides compounds generallydefined by Formula III,

or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,derivative or prodrug thereof, wherein

A is R¹—C(═O)—, R¹—OC(═O)—, R¹—NHC(═O)—, R¹—S(═O)_(b)— orR¹—NHS(═O)_(b)—, wherein

-   -   b is 1 or 2; and    -   R¹ is a partially or fully saturated 3-8 membered monocyclic,        6-12 membered bicyclic, or 7-14 membered tricyclic ring system,        said ring system formed of carbon atoms and optionally including        1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or        1-9 heteroatoms if tricyclic, said heteroatoms selected from O,        N, or S, wherein said ring system is optionally substituted        independently with one or more substituents of oxo, R⁷, R⁸, R⁹,        NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷,        C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷,        NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷,        C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸,        NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷,        NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;

B is R²—(CR^(2a)R^(2a))_(h)—, R²—O—(CR^(2a)R^(2a))_(h)—,R²—S—(CR^(2a)R^(2a))_(h)— or R²—NR^(2a)—(CR^(2a)R^(2a))_(h)—, wherein

-   -   R² is C₁-C₁₀, alkyl, C₁-C₁₀ alkenyl, C₁-C₁₀, alkynyl or a        partially or fully saturated or unsaturated 3-8 membered        monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic        ring system, said ring system formed of carbon atoms optionally        including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if        bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms        selected from O, N, or S, wherein said C₁-C₁₀ alkyl, C₁-C₁₀        alkenyl, C₁-C₁₀ alkynyl is optionally substituted independently        with one or more substituents of R⁹, and said ring system is        optionally substituted independently with one or more        substituents of oxo, R⁷, R⁸, R⁹, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸,        SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)NR⁷R⁷,        C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷,        NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸,        NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸,        S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸,        NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸;    -   each R^(2a), independently, is H, OH, NO₂, CN, NH₂, C₁-C₁₀        alkyl, C₁-C₁₀ alkoxyl or haloalkyl; and    -   h is 0, 1 or 2;

i is 1, 2 or 3;

j is 0, 1 or 2;

each R³, independently, is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R⁸ or R⁹;

R⁴ is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of R⁸ or R⁹;

R⁵ is

wherein X¹ is C(═O), O, S or NR¹²;

-   -   each X², independently, is CR¹²R¹²;    -   each of Y¹, Y² and Y³, independently, is CR¹²R¹², O, S or NR¹²;    -   m is 0, 1 or 2; and    -   o is 0, 1, 2, 3, 4 or 5;    -   provided that (a) no more than two of Y¹, Y² and Y³ is O, S or        NR¹² and (b) when    -   o is 0, then each of Y¹ and Y² is CR¹²R¹²;

R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with 1-5 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹,C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁸, C(O)NR⁸R⁹, C(O)NR⁹R⁹,NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹;

R⁸ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from O, N, or S, andoptionally substituted independently with 1-5 substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

R¹⁰ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

R¹¹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl;

alternatively, R¹⁰ and R¹¹ taken together with the carbon or nitrogenatoms to which they are attached form a partially or fully saturated orunsaturated 5-6 membered second ring of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N, or S, the second ringoptionally substituted independently with 1-5 substituents of R¹², R¹³,R¹⁴ or R¹⁵ and optionally fused to a 4-7 membered third ring, the thirdring formed of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-5 substituents of R¹², R¹³, R¹⁴ or R¹⁵;

R¹² is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 3-8 membered monocyclicor a 6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl, phenyl or R¹⁴;

R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴; SR¹⁴, OR¹⁵; SR¹⁵, C(O)R¹⁴, OC(O)R¹⁴,COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵, C(O)NR¹⁵R¹⁵,NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵, NR¹⁵C(O)NR¹⁴R¹⁵,NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵), OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵,S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵, S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵,NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ or NR¹⁵S(O)₂R¹⁵;

R¹⁴ is a saturated or partially or fully unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R¹⁵; and

R¹⁵ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, oxo, acetyl, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-thioalkoxyl or a partially or fully saturated or unsaturated 3-8membered monocyclic or 6-12 membered bicyclic ring system, said ringsystem formed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, and optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, acetyl, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, benzyl or phenyl.

In another embodiment, the compounds of Formula III include eachindependent embodiment, as described herein for variables A, B, R¹,R^(1a), R^(1b), R^(1c), R^(1d), R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, R¹⁵, W, V, X¹, X², Y¹, Y², Y³, Z¹ and Z² forcompounds of Formula I, independently, in conjunction with any of theabove or below embodiments for compounds of Formula III.

In another embodiment, the invention provides each of the compounds, andstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, and intermediates described in each ofthe examples herein.

DEFINITIONS

The following definitions should assist in understanding the inventiondescribed herein.

The term “comprising” is meant to be open ended, including the indicatedcomponent(s), but not excluding other elements.

The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

The term “C_(α-β)alkyl”, when used either alone or within other termssuch as “haloalkyl” and “alkylamino”, embraces linear or branchedradicals having α to β number of carbon atoms (such as C₁-C₁₀). One ormore carbon atoms of the “alkyl” radical may be substituted, such aswith a cycloalkyl moeity. Examples of “alkyl” radicals include methyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, ethyl,cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, n-propyl,isopropyl, n-butyl, cyclopropylbutyl, isobutyl, sec-butyl, tert-butyl,pentyl, isoamyl, hexyl and the like. The term “alkylenyl” embracesbridging divalent alkyl radicals such as methylenyl and ethylenyl.

The term “alkenyl”, when used alone or in combination, embraces linearor branched radicals having at least one carbon-carbon double bond in amoiety having between two and ten carbon atoms. Included within alkenylradicals are “lower alkenyl” radicals having two to about six carbonatoms and, for example, those radicals having two to about four carbonatoms. Examples of alkenyl radicals include, without limitation,ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Theterms “alkenyl” and “lower alkenyl”, embrace radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations, asappreciated by those of ordinary skill in the art.

The term “alkynyl”, when used alone or in combination, denotes linear orbranched radicals having at least one carbon-carbon triple bond andhaving two to ten carbon atoms. Examples of alkynyl radicals include“lower alkynyl” radicals having two to about six carbon atoms and, forexample, lower alkynyl radicals having two to about four carbon atoms.Examples of such radicals include, without limitation, ethynyl, propynyl(propargyl), butynyl, and the like.

The term “C_(α-β)alkoxyl” when used alone or in combination, embraceslinear or branched oxygen-containing alkyl radicals each having α to βnumber of carbon atoms (such as C₁-C₁₀). The terms “alkoxy” and“alkoxyl”, when used alone or in combination, embraces linear orbranched oxygen-containing radicals each having alkyl and substitutedalkyl portions of one or more carbon atoms. Examples of such radicalsinclude methoxy, ethoxy, propoxy, butoxy and tent-butoxy. Alkoxyradicals may be further substituted with one or more halo atoms, such asfluoro, chloro or bromo, to provide “haloalkoxy” radicals or with othersubstitution. Examples of such radicals include fluoromethoxy,chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy,fluoropropoxy and cyclopropylmethoxy.

The term “aryl”, when used alone or in combination, means a carbocyclicaromatic moiety containing one, two or even three rings wherein suchrings may be attached together in a fused manner. Every ring of an“aryl” multi-ring system need not be aromatic, and the ring(s) fused tothe aromatic ring may be partially or fully unsaturated and include oneor more heteroatoms selected from nitrogen, oxygen and sulfur. Thus, theterm “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,benzodioxazinyl, and the like. The “aryl” group may be substituted, suchas with 1 to 5 substituents including lower alkyl, hydroxyl, halo,haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and the like.Phenyl substituted with —O—CH₂—O— or —O—CH₂—CH₂—O— forms an arylbenzodioxolyl substituent.

The term “carbocyclic”, also referred to herein as “cycloalkyl”, whenused alone or in combination, means a partially or fully saturated ringmoiety containing one (“monocyclic”), two (“bicyclic”) or even three(“tricyclic”) rings wherein such rings may be attached together in afused manner and formed from carbon atoms. Examples of saturatedcarbocyclic radicals include saturated 3 to 6-membered monocyclic groupssuch as cyclopropane, cyclobutane, cyclopentane and cyclohexane.

The terms “ring” and “ring system” refer to a ring comprising thedelineated number of atoms, the atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. Where the number ofatoms is not delineated, such as a “monocyclic ring system” or a“bicyclic ring system”, the numbers of atoms are 5-8 for a monocyclicand 6-12 for a bicyclic ring. The ring itself, as well as anysubstitutents thereon, may be attached at any atom that allows a stablecompound to be formed. The term “nonaromatic” ring or ring system refersto the fact that at least one, but not necessarily all, rings in abicyclic or tricyclic ring system is nonaromatic.

The term “cycloalkenyl”, when used alone or in combination, means apartially or fully saturated cycloalkyl containing one, two or eventhree rings in a structure having at least one carbon-carbon double bondin the structure. Examples of cycloalkenyl groups include C₃-C₆ rings,such as compounds including, without limitation, cyclopropene,cyclobutene, cyclopentene and cyclohexene. The term also includescarbocyclic groups having two or more carbon-carbon double bonds such as“cycloalkyldienyl” compounds. Examples of cycloalkyldienyl groupsinclude, without limitation, cyclopentadiene and cycloheptadiene.

The term “halo”, when used alone or in combination, means halogens suchas fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, when used alone or in combination, embracesradicals wherein any one or more of the alkyl carbon atoms issubstituted with halo as defined above. For example, this term includesmonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as aperhaloalkyl. A monohaloalkyl radical, for example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. Examples of haloalkyl radicalsinclude fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl”, asused herein, refers to alkyl radicals having all hydrogen atoms replacedwith fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “heteroaryl”, as used herein, either alone or in combination,means a fully unsaturated (aromatic) ring moiety formed from carbonatoms and having one or more heteroatoms selected from nitrogen, oxygenand sulfur. The ring moiety or ring system may contain one(“monocyclic”), two (“bicyclic”) or even three (“tricyclic”) ringswherein such rings are attached together in a fused manner. Every ringof a “heteroaryl” ring system need not be aromatic, and the ring(s)fused thereto (to the heteroaromatic ring) may be partially or fullysaturated and optionally include one or more heteroatoms selected fromnitrogen, oxygen and sulfur. The term “heteroaryl” does not includerings having ring members of —O—O—, —O—S— or —S—S—.

Examples of unsaturated heteroaryl radicals, include unsaturated 5- to6-membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms,including for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] andtetrazole; unsaturated 7- to 10-membered heterobicyclyl groupscontaining 1 to 4 nitrogen atoms, including for example, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and thelike; unsaturated 5- to 6-membered heteromonocyclic group containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heterocyclic”, when used alone or in combination, means apartially or fully saturated ring moiety containing one, two or eventhree rings wherein such rings may be attached together in a fusedmanner, formed from carbon atoms and including one more heteroatomsselected from N, O or S. Examples of saturated heterocyclic radicalsinclude saturated 3 to 6-membered heteromonocyclic groups containing 1to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

The term “heterocycle” also embraces radicals where heterocyclicradicals are fused/condensed with aryl radicals: unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals.

Examples of partially saturated and fully saturated heterocyclylsinclude, without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “alkylamino” includes “N-alkylamino” where amino radicals areindependently substituted with one alkyl radical. Preferred alkylaminoradicals are “lower alkylamino” radicals having one to six carbon atoms.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Examples of such lower alkylamino radicals includeN-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino and thelike.

The term “dialkylamino” includes “N,N-dialkylamino” where amino radicalsare independently substituted with two alkyl radicals. Preferredalkylamino radicals are “lower alkylamino” radicals having one to sixcarbon atoms. Even more preferred are lower alkylamino radicals havingone to three carbon atoms. Examples of such lower alkylamino radicalsinclude N,N-dimethylamino, N,N-diethylamino, and the like.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes —CO₂H.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—. “Carbonyl” is also used hereinsynonymously with the term “oxo”.

The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

The term “alkylthio” or “thioalkoxy” embraces radicals containing alinear or branched alkyl radical, of one to ten carbon atoms, attachedto a divalent sulfur atom. An example of “alkylthio” or “thioalkoxy” ismethylthio, (CH₃S—).

The term “haloalkylthio” embraces radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.An example of “haloalkylthio” is trifluoromethylthio.

The term “alkylaminoalkyl” embraces alkyl radicals substituted withalkylamino radicals. Examples of alkylaminoalkyl radicals include “loweralkylaminoalkyl” radicals having alkyl radicals of one to six carbonatoms. Suitable alkylaminoalkyl radicals may be mono or dialkylsubstituted, such as N-methylaminomethyl, N,N-dimethyl-aminoethyl,N,N-diethylaminomethyl and the like.

The term “alkylaminoalkoxy” embraces alkoxy radicals substituted withalkylamino radicals. Examples of alkylaminoalkoxy radicals include“lower alkylaminoalkoxy” radicals having alkoxy radicals of one to sixcarbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkylsubstituted, such as N-methylaminoethoxy, N,N-dimethylaminoethoxy,N,N-diethylaminoethoxy and the like.

The term “Formula I” includes any sub formulas, such as Formula II.Similarly, the term “Formula II” includes any sub formulas and “FormulaIII” includes any sub formulas.

The term “pharmaceutically-acceptable” when used with reference to acompound of Formulas I-III is intended to refer to a form of thecompound that is safe for administration. For example, a salt form, asolvate, a hydrate or derivative form of a compound of Formula I, II orof Formula III, which has been approved for mammalian use, via oralingestion or other routes of administration, by a governing body orregulatory agency, such as the Food and Drug Administration (FDA) of theUnited States, is pharmaceutically acceptable.

Included in the compounds of Formulas I-III are the pharmaceuticallyacceptable salt forms of the free-base compounds. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. As appreciated by those of ordinary skill in the art, salts maybe formed from ionic associations, charge-charge interactions, covalentbonding, complexation, coordination, etc. The nature of the salt is notcritical, provided that it is pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compounds ofFormulas I-III may be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, hydrofluoric, nitric, carbonic, sulfuric and phosphoricacid. Appropriate organic acids may be selected from aliphatic,cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic andsulfonic classes of organic acids, examples of which include, withoutlimitation, formic, acetic, adipic, butyric, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,thiocyanic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid.

Suitable pharmaceutically-acceptable base addition salts of compounds ofFormulas I, II and III include metallic salts, such as salts made fromaluminum, calcium, lithium, magnesium, potassium, sodium and zinc, orsalts made from organic bases including, without limitation, primary,secondary and tertiary amines, substituted amines including cyclicamines, such as caffeine, arginine, diethylamine, N-ethyl piperidine,histidine, glucamine, isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine, piperidine, triethylamine, disopropylethylamineand trimethylamine All of these salts may be prepared by conventionalmeans from the corresponding compound of the invention by reacting, forexample, the appropriate acid or base with the compound of FormulasI-III.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides, and others. Water or oil-soluble ordispersible products are thereby obtained.

Examples of acids that may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, citric acid, sulphuric acid andphosphoric acid and such organic acids as oxalic acid, stearic and,salicylic acid, pamoic acid, gluconic acid, ethanesulfonic acid,methanesulfonic acid, toluenesulfonic acid, tartaric acid, fumaric acid,medronic acid, napsylic acid, maleic acid, succinic acid and citricacid. Other examples include salts with alkali metals or alkaline earthmetals such as sodium, potassium, calcium or magnesium, or with organicbases.

Additional examples of such salts can be found in Berge et al., J.Pharm. Sci., 66:1 (1977). Conventional methods may be used to form thesalts. For example, a phosphate salt of a compound of the invention maybe made by combining the desired compound free base in a desiredsolvent, or combination of solvents, with phosphoric acid in a desiredstoichiometric amount, at a desired temperature, typically under heat(depending upon the boiling point of the solvent). The salt can beprecipitated upon cooling (slow or fast) and may crystallize (i.e., ifcrystalline in nature), as appreciated by those of ordinary skill in theart. Further, hemi-, mono-, di, tri- and poly-salt forms of thecompounds of the present invention are also contemplated herein.Similarly, hemi-, mono-, di, tri- and poly-hydrated forms of thecompounds, salts and derivatives thereof, are also contemplated herein.

The term “derivative” is broadly construed herein, and intended toencompass any salt of a compound of this invention, any ester of acompound of this invention, or any other compound, which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to the ability to modulate anenzyme.

The term “pharmaceutically-acceptable derivative” as used herein,denotes a derivative which is pharmaceutically acceptable.

The term “prodrug”, as used herein, denotes a compound which uponadministration to a subject or patient is capable of providing (directlyor indirectly) a compound of this invention. Examples of prodrugs wouldinclude esterified or hydroxylated compounds where the ester or hydroxylgroups would cleave in vivo, such as in the gut, to produce a compoundaccording to Formula I-III. A “pharmaceutically-acceptable prodrug” asused herein, denotes a prodrug which is pharmaceutically acceptable.Pharmaceutically acceptable modifications to the compounds of FormulaI-III are readily appreciated by those of ordinary skill in the art.

The compound(s) of Formulas I-III may be used to treat a subject byadministering the compound(s) as a pharmaceutical composition. To thisend, the compound(s) can be combined with one or more carriers, diluentsor adjuvants to form a suitable composition, which is described in moredetail herein.

The term “carrier”, as used herein, denotes any pharmaceuticallyacceptable additive, excipient, adjuvant, or other suitable ingredient,other than the active pharmaceutical ingredient (API), which istypically included for formulation and/or administration purposes.“Diluent” and “adjuvant” are defined hereinafter.

The terms “treat”, “treating,” “treatment,” and “therapy” as used hereinrefer to therapy, including without limitation, curative therapy,prophylactic therapy, and preventative therapy. Prophylactic treatmentgenerally constitutes either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals.

The phrase “effective dosage amount” is intended to quantify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies. Accordingly, this term is not limited to a singledose, but may comprise multiple dosages required to bring about atherapeutic or prophylactic response in the subject. For example,“effective dosage amount” is not limited to a single capsule or tablet,but may include more than one capsule or tablet, which is the doseprescribed by a qualified physician or medical care giver to thesubject.

The term “leaving group” (also denoted as “LG”) generally refers togroups that are displaceable by a nucleophile. Such leaving groups areknown in the art. Examples of leaving groups include, but are notlimited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate,tosylate), sulfides (e.g., SCH₃), N-hydroxsuccinimide,N-hydroxybenzotriazole, and the like. Nucleophiles are species that arecapable of attacking a molecule at the point of attachment of theleaving group causing displacement of the leaving group. Nucleophilesare known in the art. Examples of nucleophilic groups include, but arenot limited to, amines, thiols, alcohols, Grignard reagents, anionicspecies (e.g., alkoxides, amides, carbanions) and the like.

General Synthetic Procedures

The present invention further comprises procedures for the preparationof compounds of Formulas I, II and III.

The compounds of Formulas I, II and III can be synthesized according tothe procedures described in the following Schemes 1-5, wherein thesubstituents are as defined for Formulas I, II and III above, exceptwhere further noted. The synthetic methods described below are merelyexemplary, and the compounds of the invention may also be synthesized byalternate routes utilizing alternative synthetic strategies, asappreciated by persons of ordinary skill in the art.

The following list of abbreviations used throughout the specificationrepresent the following and should assist in understanding theinvention:

-   ACN, MeCN—acetonitrile-   BOP—benzotriazol-1-yl-oxy hexafluorophosphate-   Cs₂CO₃—cesium carbonate-   CHCl₃—chloroform-   CH₂Cl₂, DCM—dichloromethane, methylene chloride-   CuI—copper iodide-   DCC—dicyclohexylcarbodiimide-   DIC—1,3-diisopropylcarbodiimide-   DIEA, DIPEA—diisopropylethylamine-   DME—dimethoxyethane-   DMF—dimethylformamide-   DMAP—4-dimethylaminopyridine-   DMS—dimethylsulfide-   DMSO—dimethylsulfoxide-   EDC, EDCI—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   FBS—fetal bovine serum-   G, gm—gram-   h, hr—hour-   H₂—hydrogen-   H₂O—water-   HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   HBr—hydrobromic acid-   HCl—hydrochloric acid-   HOBt—1-hydroxybenzotriazole hydrate-   HOAc—acetic acid-   HPLC—high pressure liquid chromatography-   IPA, IpOH—isopropyl alcohol-   K₂CO₃—potassium carbonate-   KI—potassium iodide-   LG—leaving group-   LiOH—lithium hydroxide-   MgSO₄—magnesium sulfate-   MS—mass spectrum-   MeOH—methanol-   N₂—nitrogen-   NaCNBH₃—sodium cyanoborohydride-   Na₂CO₃—sodium carbonate-   NaHCO₃—sodium bicarbonate-   NaH—sodium hydride-   NaBH₄—sodium borohydride-   NaOH—sodium hydroxide-   Na₂SO₄—sodium sulfate-   NH₄Cl—ammonium chloride-   NH₄OH—ammonium hydroxide-   P(t-bu)₃—tri(tert-butyl)phosphine-   PBS—phosphate buffered saline-   Pd/C—palladium on carbon-   Pd(PPh₃)₄—palladium(0)triphenylphosphine tetrakis-   Pd(dppf)Cl₂—palladium(1,1-bisdiphenylphosphinoferrocene) II chloride-   Pd(PhCN)₂Cl₂—palladium di-cyanophenyl dichloride-   Pd(OAc)₂—palladium acetate-   Pd₂(dba)₃—bis(dibenzylideneacetone) palladium-   PyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium    hexafluorophosphate-   RT, rt—room temperature-   RBF, rbf—round bottom flask-   TBTU—O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   TEA, Et₃N—triethylamine-   TFA—trifluoroacetic acid-   THF—tetrahydrofuran-   UV—ultraviolet light

While the synthetic strategy for preparing the compounds of Formulas I,II and III may vary, as appreciated by persons skilled in the art, onestrategy for devising a method of making compounds of these formulas isby retro-synthetic disconnection. For example,

as shown in Formulas I-III above, each squiggly line represents apossible point of bond-construction, whose order is generally dependentupon the particular compound being synthesized. Such bond constructionmethods are generally described in synthetic schemes 1-5 below.

Scheme 1 describes one method of preparing an R¹-substituted carboxylicacids 4 and 5, which may then be used to couple to an amine to make anR¹-amide linked A group, or converted to an isocyanate which can then becoupled to an amine to make an R¹-urea linked A group (where W=—C(O)— or—NHC(O)—). An ester-halo (X=halogen such as Br or I) substituted R¹ ringcompound 4 or 5, both of which include a substitutable nitrogen in thering, and which are generally referred to herein as the left-handportion of the compounds of Formulas I, II and III, can be preparedaccording to the method generally described in Scheme 1. As shown, amethyl ester-halo substituted compound 1 can be reacted in aMitsunobu-type reaction with a desired hydroxyl-substituted R^(1a)compound under suitable conditions, such as in the presence oftri-phenyl phosphine and diethylazodicarboxylate (commonly referred toas DEAD) for a suitable time period to form the ring N—R^(1a)substituted adduct 2. Intermediate 2 may also be formed using a suitablereductive amination method as well utilizing an aldehyde, for example(not shown in scheme 1). Compound 2 can be reacted in apalladium-catalyzed coupling reaction, such as a suzuki-type reaction,in the presence of suitable solvents and accompanying reagents, such asa base, to form the R¹—R^(1b) substituted compound 3. Formation ofcompound 3 may require heat, up to and including reflux temperaturesdepending on the particular substrate, solvent and reagent(s)concentration, as appreciated by those skilled in the art. Compound 3can then be hydrolyzed in the presence of a suitable base and solvent toform the corresponding acid-adduct 4. Acid 4 is then utilized as anintermediate to couple, as described in Scheme 2 below, with desiredintermediates or other building blocks to make compounds of FormulasI-III.

Alternatively, compound 1 can be hydrolyzed directly to thecorresponding acid 5. Ester-Halo-substituted compound 5 is a usefulintermediate for coupling the backbone core compounds with desired B, R³and R⁴ substitutions already in place. Compound 5 can then be modifiedto include desirable R¹ substitutions, including R^(1a), R⁷, R⁸ and R⁹groups. In this fashion, analogs of a variety of desired left-handpieces of compounds of Formulas I-III may be readily synthesized (seeScheme 3).

R¹ ring systems, which may be substituted with various substitutionsincluding one or more R⁷, R⁸ or R⁹ groups, can be coupled to the corehydroxyl-propyl, hydroxyl-butyl or hydroxyl-pentyl backbone structure,generally designated in Scheme 2 as “Pr” group, by various couplingmethods as described in Scheme 2. In each of the 4 sub-schemes, X refersgenerally to a “leaving group” such as a halide (bromine, chlorine,iodine or fluorine), alkylsulfonate and other known groups (also seedefinitions herein) which generally forms an electrophilic species (E⁺)and m is an integer from 0-1. The NH₂ group (primary amine) is anucleophilic species (Nu⁻), as is secondary amines, hydroxides,alkoxides, an anionic carbon species and the like, which should besufficiently strong to the attack the E⁺ species and displace theleaving group X thereby effecting a coupling of ring R¹ to the Prbackbone. Examples of suitable electrophilic carbonyl species include,without limitation, acid halides, mixed anhydrides, aldehydes,carbamoyl-chlorides, sulfonyl chlorides, acids activated by couplingwith activating reagents such as TBTU, HBTU, HATU, HOBT, BOP, PyBOP andcarbodiimides (DCC, EDC and the like), and other electrophilic speciesincluding halides, isocyanates, daizonium ions and the like.

The coupled adduct of R¹ and Pr, shown as products in sub-schemes 1-4,can be brought about using various conventional methods. For example, anamide or a sulfonamide linkage, as shown in sub-schemes 2 and 4, can bemade utilizing an amine on the Pr intermediate and an activatedelectrophilic species, on the R¹ ring such as the acid chloride orsulfonyl chloride as shown. The reaction proceeds generally in thepresence of a suitable solvent and/or base. Suitable solvents include,without limitation, generally non-nucleophilic, anhydrous solvents suchas toluene, CH₂Cl₂, THF, DMF, DMSO, N,N-dimethylacetamide and the like,including solvent combinations thereof. The solvent may range inpolarity, as appreciated by those skilled in the art. Suitable basesinclude, for example, tertiary amine bases such as DIEA, TEA, carbonatebases such as Na₂CO₃, K₂CO₃, Cs₂CO₃, hydrides such as NaH, KH,borohydrides, cyanoborohydrides and the like, alkoxides such as NaOCH₃,and the like. The base itself may also serve as a solvent. The reactionmay optionally be run neat, i.e., without any base and/or solvent. Thesecoupling reactions are generally fast and conversion occurs typically inambient conditions. However, depending upon the particular substrate,such reactions may require heat, as appreciated by those skilled in theart.

Similarly, carbamates as illustrated in sub-scheme 1 and ureas asillustrated in sub-scheme 3 may be made as shown, wherein X has the samedefinition as above, using the same coupling methods described above forsub-schemes 2 and 4. While the above methods are so described, they arenot exhaustive, and other methods for linking R¹ rings and desired Prgroups together may be utilized as appreciated by those skilled in theart.

The coupling methods described in sub-schemes 1-4 of scheme 2 are alsoapplicable for coupling desired R¹ rings to desired Pr intermediates notcontaining desired R⁵ groups, although sub-schemes 1-4 as illustrated docontain R⁵ groups.

Amine intermediate 9 (j=0) can be prepared according to the methodgenerally described in Scheme 3. As shown, spiro-substituted- orgem-dialky-substituted (not shown) oxo-R⁵ ring intermediates 6 can beconverted directly to the amino-intermediate 9 using known reductiveamination methods, such as in the presence of sodium cyanoborohydrideand ammonium acetate. Alternatively, the carbonyl of R⁵ may be reducedto the corresponding alcohol using conventional reducing reagents, andthen displaced to form the corresponding azido-intermediate 8 usingknown reagents, such as DPPA, in the presence of a suitable base asshown. Intermediate 8 may be reduced with a suitable reducing agent orby known methods, including triphenylphosphene, trimethylphosphene orlithium aluminum hydride (LAH), to produce the desired amino adduct 9.

Yet another method of forming the amine adduct 9, can be via an imineformation to form compound 10. The imine double bond of compound 10 maythen be successively reduced and hydrolyzed to yield the primary amineproduct 9. Such steps may be conducted using known, convention methods,as appreciated by those skilled in the art.

Scheme 4 describes, generally, multiple different methods forconstructing the bond between the Pr starting material or intermediate12′ (sub-scheme 1) or 12 (sub-scheme 2) and an R⁵ ring intermediate 9,thereby synthesizing a desired intermediate 14′ or a final compound 14of Formulas I-III. One method to make this bond is to react an epoxideintermediate 12 or 12′ (Note: the epoxide 12 or 12′ may be purchasedcommercially or made via known, published methods such as from theolefin precursor), with an amino-R⁵ intermediate 9, as shown. Thereaction may proceed in the presence of a polar solvent, such as analcohol or dioxanes, and may require additional reagents, as appreciatedby those skilled in the art. Additionally, the reaction may require heatfor a period of time. Note that while the scheme described the additiono heat, this is by way of example, and not every reaction would requireheat as appreciated by those of ordinary skill in the art. Theprotecting group may be removed using an acid, such as HCl, such thatthe bonded adduct 14′ is recovered as an HCl salt.

Alternatively, desired intermediates 14′ may be synthesized startingwith an amine-protected aldehyde intermediate 13′ (sub-scheme 3) or 13(sub-scheme 4) and condensing the aldehyde with a primary or secondaryamine 9 to form an imine (not shown, generally formed in-situ and notisolated). The imine can then be reduced using a known reducing agent,such as a hydride or borohydride, the reduced intermediate may bedeprotected to provide an intermediate 14′ having an amine useful toprepare compounds 14 of Formulas I-III.

Scheme 5 describes, generally, two different methods (Methods A and B)for constructing intermediates 18′ (Method A) or 18 (Method B) which areuseful for making compounds of Formula III. As shown in Method A, theacid group of an olefinic amino-acid compound 15 may be modified with adesired B group to form a compound 16, by first activating the acid of15 with a known activating agent, such as HATU in the presence of asuitable base, and treating activated 15 with a B-substituted grignardreagent or B-ligand metal reagent, which delivers the desired B group todisplace the carbonyl activating group and form compound 16. Compound 16may be oxidized to the corresponding ketone 17 by known methods, such aswith sodium periodiate and osmium tetroxide. Ketone 17 may then bereacted with amine 9, via a reductive amination step, to form an aminoprotected intermediate, which can be deprotected to yield intermediate18′, as shown.

Alternatively, intermediate 18 may be made using a reductive aminationstep with an amine-protected diamine compound 19 and a ketone 6. Suchreductive amination step may be employed with conventional conditionsusing known reducing reagents in suitable solvents, at suitabletemperatures, as appreciated by one of ordinary skill in the art.

To enhance the understanding and appreciation of the present invention,the following specific examples (starting reagents, intermediates andcompounds of Formulas I-III) are set forth. The following analyticalmethods were used to purify and/or characterize the compounds, andintermediates, described in the examples below.

Analytical HPLC and LC-MS Methods:

Unless otherwise indicated, all analytical HPLC analyses were run on anAgilent Model 1100 series system LC/MSD SL using one of the twofollowing Columns: (a) Phenomenex Sernegi (4 micron, C18, 50×2 mm) or(b) a Gemini column (5 micron, C18, 100×2 mm). A typical run through theinstrument included: eluting at 1 ml/min with an linear gradient of 10%(v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 10 minutes;conditions may be varied to achieve optimal separation.

Preparative HPLC Method:

Unless otherwise indicated, the compounds described herein were purifiedvia reverse phase HPLC using one of the following instruments: Shimadzu,varian, Gilson; utilizing one of the following two HPLC columns: (a) aPhenomenex Luna or (b) a Gemini column (5 micron or 10 micron, C18,150×50 mm)

A typical run through the instrument included: eluting at 45 ml/min witha linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v TFA) in water(0.1% TFA) over 10 minutes; conditions can be varied to achieve optimalseparations.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Brukerseries 300 MHz instrument or a Bruker series 400 MHz instrument. Whereso characterized, all observed protons are reported as parts-per-million(ppm) downfield from tetramethylsilane (TMS) or other internal referencein the appropriate solvent indicated.

Mass Spectra (MS)

Unless otherwise indicated, all mass spectral data for startingmaterials, intermediates and/or exemplary compounds are reported asmass/charge (m/z), having an (M+H⁺) molecular ion. The molecular ionreported was obtained by electrospray detection method (commonlyreferred to as an ESI MS) utilizing a PE SCIEX API 150EX MS instrument.

Compounds having an isotopic atom, such as bromine and the like, aregenerally reported according to the detected isotopic pattern, asappreciated by those skilled in the art.

Naming Convention

The compounds disclosed and described herein have been named using thenaming convention provided with Chem-Draw Ultra 8.0 software, availablein Chem Office. In some instances, compounds were named with the term“spirocarbocycle” inserted where appropriate. For example, where thechroman is substituted with 2,2-spirocyclobutyl, “2,2-spirocyclobutyl”is added to the Chem-Draw nomenclature in the appropriate place.Chem-Draw utilizes the ISIS Draw software compound naming convention, asappreciated by those skilled in the art.

EXAMPLES

The Examples, described herein below, represent various exemplarystarting materials, intermediates and compounds of Formulas I-III, whichshould assist in a better understanding and appreciation of the scope ofthe present invention and of the various methods which may be used tosynthesize compounds of Formulas I, II and III. It should be appreciatedthat the general methods above and specific examples below areillustrative only, for purpose of assistance in understanding theinvention, and should not be construed as limiting the scope of thepresent invention in any manner.

Example 1

5-cyano-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamideStep 1: Methyl5-cyano-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate

A mixture of methyl5-bromo-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (500 mg,1.67 mmol), tris(dibenzylideneacetone)dipalladium (31 mg, 0.033 mmol),DPPF (37 mg, 0.07 mmol), Zinc (13 mg, 0.20 mmol) and zinc cyanide (120mg, 1.00 mmol) was purged with nitrogen, followed by the addition ofdimethylacetamide (3.3 mL). The resulting mixture was heated to 120° C.for 2 h. The mixture was brought to room temperature, diluted inethylacetate and washed with saturated NH₄Cl. The organic phase wasseparated, washed again with saturated NH₄Cl, brine, dried andchromatographed on silica gel using 3:1 hexanes:ethylacetate to affordthe title compound as a yellow oil. MS m/z: 247 (M+1).

Step 2: 5-Cyano-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylicacid

A mixture of Methyl5-cyano-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (290 mg,1.2 mmol) and 1N sodium hydroxide (6 mL, 6.0 mmol) in methanol (12 mL)was heated to reflux for 1 h and brought to RT. The mixture wasconcentrated and the residue obtained was dissolved in ethylacetate (20mL), acidified with 1N hydrochloric acid (pH ˜5). The organic phase wasseparated, dried over magnesium sulfate and concentrated to afford thetitle compound as a light yellow solid. MS m/z: 233 (M+1).

Step 3:5-cyano-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

To a solution of5-cyano-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (50mg, 0.20 mmol) in N—N-dimethylformamide (2 mL) was addedN—N-diisopropylethylamine (70 uL, 0.40 mmoL) and stirred at roomtemperature. After 5 min, 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide(78 mg, 0.40 mmoL),(2S,3R)3-amino-1-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-olhydrochloride (110 mg, 0.26 mmol) and HBTU (72 mg, 0.20 mmol) wereadded. The resulting solution was stirred at room temperature for 20 h.The mixture was poured into water (8 mL) and extracted withethylacetate. The organic extracts were combined, washed with saturatedNH₄Cl (3×), brine, dried over magnesium sulfate, concentrated, andpurified by HPLC to afford the title compound as an off-white solid. MSm/z: 609 (M+1).

Example 2

1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamideStep 1: Methyl 1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate

Through a solution of methyl5-bromo-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (300 mg, 1mmol) and Pd/C (300 mg) in methanol (30 mL) was bubbled H₂ through aballoon for 48 h. The mixture was filtered through Celite® andconcentrated to afford the title compound. MS m/z: 222 (M+1).

Step 2: 1-Cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

The title compound was obtained using a procedure analogous to thatdescribed in Example 1, with methyl1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate. MS m/z: 208(M+1).

Step 3:1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained using a procedure analogous to thatdescribed in Example 1, with1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (50 mg, 0.24mmol) and(2S,3R)-3-amino-1-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-olhydrochloride (120 mg, 0.29 mmol). MS m/z: 584 (M+1).

Example 3

1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-5-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide

A mixture of 2-fluoroboronic acid (50 mg, 0.36 mmol),5-bromo-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide(200 mg, 0.30 mmol), tetrakis(triphenylphosphine) palladium (0) (17 mg,0.015 mmol) and sodium carbonate (160 mg, 1.5 mmol) was purged withnitrogen for 10 min, followed by the addition of dioxane (3 mL). Theresulting yellow suspension was heated to reflux for 3 h and brought toroom temperature. The mixture was diluted in EtOAc, washed withsaturated NaHCO₃, brine, dried over MgSO₄ and chromatographed by HPLC toafford the title compound as a white-solid. MS m/z: 678 (M+1).

Example 4

5-Bromo-1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained using a procedure analogous to thatdescribed in Example 1, with5-bromo-1-Cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (700mg, 2.5 mmol) andN-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutanediamine(1.3 g, 3.0 mmol) to afford the title compound as a light yellow oil. MSm/z: 662 (M+1).

Example 5

A mixture of5-Bromo-1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide(200 mg, 0.30 mmol), 2-tri-methylstannylpyridine (87 mg, 0.36 mmol),tris(dibenzylideneacetone)dipalladium (4.1 mg, 0.0045 mmol),tri-tert-butylphosphine (3.6 mg, 0.018 mmol), cesium fluoride (100 mg,0.66 mmol) in dioxane (2 mL) was heated to 100° C. for 17 h. The mixturewas brought to room temperature, diluted with ethylacetate, washed withwater, saturated NaHCO₃, dried over MgSO₄, concentrated and purified byHPLC to afford the title compound as a white solid. MS m/z: 661 (M+1).

Example 6

1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-5-(1H-pyrazol-1-yl)-1,6-dihydropyridine-3-carboxamideStep 1: Methyl1-cyclopentyl-6-oxo-5-(1H-pyrazol-1-yl)-1,6-dihydropyridine-3-carboxylate

A mixture of methyl5-bromo-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (300 mg,1.00 mmol), pyrazole (23 mg, 0.34 mmol), K₂CO₃ (99 mg, 0.72 mmol), CuI(9.1 mg, 0.048 mmol), N¹—N²-dimethylethane-1,2-diamine (5 uL, 0.048mmol) in toluene (3 mL) was heated to 100° C. for 17 h. The mixture wasbrought to RT and quenched with saturated NH₄Cl, brine, dried over MgSO₄and chromatographed on silica gel using 3:1 hexanes:ethylacetate toafford the title compound as a white solid. MS m/z: 288 (M+1).

Step 2:1-cyclopentyl-6-oxo-5-(1H-pyrazol-1-yl)-1,6-dihydropyridine-3-carboxylicacid

The title compound was obtained using a procedure analogous to thatdescribed in Example 1, with methyl1-cyclopentyl-6-oxo-5-(1H-pyrazol-1-yl)-1,6-dihydropyridine-3-carboxylate(60 mg, 0.21 mmol). MS m/z: 274 (M+1).

Step 3:1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-5-(1H-pyrazol-1-yl)-1,6-dihydropyridine-3-carboxamide

A mixture of5-bromo-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide(160 mg, 0.24 mmol), pyrazole (23 mg, 0.34 mmol), K₂CO₃ (99 mg, 0.72mmol), CuI (9.1 mg, 0.048 mmol), N¹—N²-dimethylethane-1,2-diamine (5 uL,0.048 mmol) in toluene (3 mL) was heated to 100° C. for 17 h. Themixture was brought to room temperature and quenched with saturatedNH₄Cl, brine, dried over MgSO₄ and chromatographed by HPLC, to affordthe title compound. MS m/z: 650 (M+1).

Example 7

1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-5-(2-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide

A mixture of 4-fluoroboronic acid (32 mg, 0.23 mmol),5-bromo-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide(125 mg, 0.19 mmol), tetrakis(triphenylphosphine) palladium (0) (11 mg,0.010 mmol) and sodium carbonate (100 mg, 0.95 mmol) was purged withnitrogen for 10 min, followed by the addition of dioxane (3 mL). Theresulting yellow suspension was heated at reflux for 3 h and brought toroom temperature. The mixture was diluted in EtOAc, washed withsaturated NaHCO₃, brine, dried over MgSO₄ and chromatographed by HPLC toafford the title compound as a white solid. MS m/z: 678 (M+1).

Example 8

1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-5-phenyl-1,6-dihydropyridine-3-carboxamide

A mixture of phenylboronic acid (26 mg, 0.22 mmol),5-bromo-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide(116 mg, 0.18 mmol), tetrakis(triphenylphosphine) palladium (0) (10 mg,0.009 mmol) and sodium carbonate (95 mg, 0.90 mmol) was purged withnitrogen for 10 min followed, by the addition of dioxane (3 mL). Theresulting yellow suspension was heated at reflux for 3 h and brought toroom temperature. The mixture was diluted in EtOAc, washed withsaturated NaHCO₃, brine, dried over MgSO₄ and chromatographed by HPLC toafford the title compound as a white-solid. MS m/z: 660 (M+1).

Example 9

1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-5-(3-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxamide

A mixture of 3-fluoroboronic acid (41 mg, 0.29 mmol),5-bromo-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide(160 mg, 0.0.24 mmol), tetrakis(triphenylphosphine) palladium (0) (14mg, 0.012 mmol) and sodium carbonate (130 mg, 1.2 mmol) was purged withnitrogen for 10 min, followed by the addition of dioxane (3 mL). Theresulting yellow suspension was heated at reflux for 3 h and brought toRT. The mixture was diluted in EtOAc, washed with saturated NaHCO₃,brine, dried over MgSO₄ and chromatographed by HPLC to afford the titlecompound as a white-solid. MS m/z: 678 (M+1).

Example 10

N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1-(3-phenylcyclopentyl)-1,6-dihydropyridine-3-carboxamideStep 1: 3-Phenylcyclopentanone

A mixture of phenylboronic acid (1.63 g, 13.4 mmol), cyclopent-2-enone(1.0 g, 10.4 mmol), and Na₂CO₃ (2.2 g, 20.8 mmol) was purged withnitrogen for 15 min followed by the addition of [Rh(cod)Cl]₂ (100 mg,0.21 mmol) and water (30 mL). The resulting suspension was heated to 80°C. for 20 min. The mixture was extracted with CH₂Cl₂, washed with brine,dried over MgSO₄ and chromatographed on silica gel using 3:1hexanes:ethylacetate to afford the title compound as a colorless oil. MSm/z: 161 (M+1).

Step 2: 3-Phenylcyclopentanol

A mixture of 3-phenylcyclopentanone (1.3 g, 8.12 mmol) and NaBH₄ (0.61g, 16.24 mmol) in methanol (15 mL) was stirred at room temperature for 1h. The mixture was concentrated, dissolved in CH₂Cl₂, washed with 10%HCl, brine, dried over MgSO₄ and concentrated to afford the titlecompound as a white solid. MS m/z: 163 (M+1).

Step 3: Methyl5-bromo-6-oxo-1-(3-phenylcyclopentyl)-1,6-dihydropyridine-3-carboxylate

To a suspension of methyl5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (1.6 g, 6.8 mmol),3-phenylcyclopentanol (1.32 g, 8.15 mmol) and triphenylphosphine (2.7 g,10.2 mmol) in dry THF (15 mL) was slowly added diethyl azodicarboxylate(1.8 g, 10.2 mmol) at RT. The resulting yellow solution was stirred atroom temperature for 17 h. The mixture was diluted in ethylacetate,washed with water, brine, dried over MgSO₄, and chromatographed onsilica gel using hexanes to 3:1 hexanes:ethylacetate, to afford thetitle compound. MS m/z: 376 (M+1).

Step 4:5-Bromo-6-oxo-1-(3-phenylcyclopentyl)-1,6-dihydropyridine-3-carboxylicacid

The title compound was obtained using a procedure analogous to thatdescribed in Example 1, with methyl5-bromo-6-oxo-1-(3-phenylcyclopentyl)-1,6-dihydropyridine-3-carboxylate(390 mg, 1.04 mmol). MS m/z: 361 (M+1).

Step 5: 6-oxo-1-(3-phenylcyclopentyl)-1,6-dihydropyridine-3-carboxylicacid

The title compound was obtained using a procedure analogous to thatdescribed in Example 2, using5-bromo-6-oxo-1-(3-phenylcyclopentyl)-1,6-dihydropyridine-3-carboxylicacid (360 mg, 1.0 mmol). MS m/z: 284 (M+1).

Step 6:N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1-(3-phenylcyclopentyl)-1,6-dihydropyridine-3-carboxamide

The title compound was obtained using a procedure analogous to thatdescribed in Example 1, using6-oxo-1-(3-phenylcyclopentyl)-1,6-dihydropyridine-3-carboxylic acid (100mg, 0.35 mmol) and(2S,3R)3-amino-1-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-olhydrochloride (180 mg, 0.42 mmol). MS m/z: 660 (M+1).

Example 11

N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-5-bromo-1-(3-phenylcyclopentyl)-1,6-dihydropyridine-3-carboxamide

The title compound may be obtained using a procedure analogous to thatdescribed in Example 1.

Example 12

N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1-(3-phenylcyclohexyl)-1,6-dihydropyridine-3-carboxamideStep 1: 3-Phenylcyclohexanone

The title compound was obtained using a procedure analogous to thatdescribed in Step 1 of Example 10 using cyclohex-2-enone (1.0 g, 10.4mmol) and phenylboronic acid (1.3 g, 10.4 mmol) to afford the titlecompound as a colorless oil. MS m/z: 175 (M+1).

Step 2: 3-Phenylcyclohexanol

The title compound was obtained using a procedure analogous to thatdescribed in Step 2 of Example 10, using 3-phenylcyclohexanone (100 mg,0.57 mmol) to afford a white solid. MS m/z: 177 (M+1).

Step 3: Methyl5-bromo-6-oxo-1-(3-phenylcyclohexyl)-1,6-dihydropyridine-3-carboxylate

The title compound was obtained using a procedure analogous to thatdescribed in Step 3 of Example 10. MS m/z: 390 (M+1).

Step 4:5-Bromo-6-oxo-1-(3-phenylcyclohexyl)-1,6-dihydropyridine-3-carboxylicacid

The title compound was obtained using a procedure analogous to thatdescribed in Step 4 of Example 10. MS m/z: 376 (M+1).

Step 5: 6-oxo-1-(3-phenylcyclohexyl)-1,6-dihydropyridine-3-carboxylicacid

The title compound was obtained using a procedure analogous to thatdescribed in Step 5 of Example 10, using5-bromo-6-oxo-1-(3-phenylcyclohexyl)-1,6-dihydropyridine-3-carboxylicacid (70 mg, 0.19 mmol). MS m/z: 298 (M+1).

Step 6:N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1-(3-phenylcyclohexyl)-1,6-dihydropyridine-3-carboxamide

The title compound was obtained using a procedure analogous to thatdescribed in Example 1, using6-oxo-1-(3-phenylcyclohexyl)-1,6-dihydropyridine-3-carboxylic acid (30mg, 0.10 mmol) and(2S,3R)3-amino-1-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-olhydrochloride (52 mg, 0.12 mmol) to afford the title compound as a whitesolid. MS m/z: 674 (M+1).

Example 13

N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-5-bromo-1-(3-phenylcyclohexyl)-1,6-dihydropyridine-3-carboxamide

The title compound may be obtained using a procedure analogous to thatdescribed in Example 1.

Example 14

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-OXO-5-(pyridine-3-yl)-1,6-dihydropyridine-3-carboxamideExample 15

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-OXO-5-(pyridin-4-yl)-1,6-dihydropyridine-3-carboxamideExample 16

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-OXO-5-(pyrimidin-5-yl)-1,6-dihydropyridine-3-carboxamide

The title compounds, Example 14, 15 and 16, were obtained using aprocedure analogous to that described in Example 8, usingpyridine-3-ylboronic acid (24 mg, 0.20 mmol),5-bromo-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide(in Ex. 14, 100 mg, 0.15 mmol); pyridine-4-ylboronic acid (26 mg, 0.21mmol),5-bromo-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide(in Ex. 15, 105 mg, 0.16 mmol) and pyrimidin-5-ylboronic acid (13 mg,0.10 mmol),5-bromo-1-cyclopentyl-N-(2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide(in Ex. 16, 50 mg, 0.08 mmol), respectively, to afford the titlecompound Example 14 as a light brown solid (MS m/z: 661 (M+1); titlecompound Example 15 as a light yellow solid; and title compound Example16 (MS m/z: 662 (M+1).

Example 17

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-OXO-5-(pyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamideStep 1: Methyl1-cyclopentyl-6-oxo-5-(pyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxylate

A mixture of methyl5-bromo-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (100 mg,0.33 mmol), pyrrolidine (33 uL, 0.40 mmol), cesium carbonate (150 mg,0.46 mmol), tris(dibenzylideneacetone)dipalladium (0) (3 mg, 0.0033mmol), rac-2-2′-bis(diphenyl-phosphino)-1,1′-binaphthyl (3.1 mg, 0.005mmol) was purged with nitrogen for 30 min, followed by the addition ofanhydrous toluene (1.5 mL). The resulting light-brown solution washeated to 95° C. for 17. The mixture was brought to room temperature andpartitioned between ethyl acetate and saturated NH₄Cl. The organic phasewas separated, washed with saturated NH₄Cl, brine, dried over MgSO₄ andchromatographed on silica gel using 3:1 hexanes:ethyl acetate to affordthe title compound as a yellow oil. MS m/z: 291 (M+1).

Step 2:1-cyclopentyl-6-oxo-5-(pyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxylicacid

The title compound was obtained using a procedure analogous to thatdescribed in Example 10, as a light green-yellow solid. MS m/z: 277(M+1).

Step 3:1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-OXO-5-(pyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide

The title compound was obtained using a procedure analogous to thatdescribed in Example 1, reacting1-cyclopentyl-6-oxo-5-(pyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxylicacid (35 mg, 0.13 mmol) and(2S,3R)3-amino-1-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-olhydrochloride (50 mg, 0.13 mmol) to afford the title compound as a lightyellow solid. MS m/z: 653 (M+1).

Example 18

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-5-(isopropylamino)-6-oxo-1,6-dihydropyridine-3-carboxamideStep 1: Methyl1-cyclopentyl-5-(isopropylamino)-6-oxo-1,6-dihydropyridine-3-carboxylate

The title compound was obtained using a procedure analogous to thatdescribed in Example 17. MS m/z: 279 (M+1).

Step 2:1-cyclopentyl-5-(isopropylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

The title compound was obtained using a procedure analogous to thatdescribed in Example 10. MS m/z: 265 (M+1).

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-5-(isopropylamino)-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained using a procedure analogous to thatdescribed in Example 1, reacting1-cyclopentyl-5-(isopropylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (22.5 mg, 0.085 mmol) and(2S,3R)3-amino-1-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-ol(34 mg, 0.085 mmol) to afford the title compound as a light yellowsolid. MS m/z: 641 (M+1).

Example 19

1-cyclopentyl-5-(dimethylamino)-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained using a procedure analogous to thatdescribed in Example 18, using1-cyclopentyl-5-(dimethylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid (25 mg, 0.10 mmol) and(2S,3R)3-amino-1-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-ol(39.4 mg, 0.10 mmol) to afford the title compound as a light yellowsolid. MS m/z: 627 (M+1).

Example 20

1-cyclopentyl-5-(dimethylamino)-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound, using a procedure analogous to that described inExample 19, was obtained as a light yellow solid. MS m/z: 613 (M+1).

Example 21

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-OXO-5-(pyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide

The title compound was obtained using a procedure analogous to thatdescribed in Example 1, as a light yellow solid. MS m/z: 639 (M+1).

Example 22

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyrazin-2-yl)-1,6-dihydropyridine-3-carboxamide

The title compound was obtained using procedures analogous to thosedescribed in Example 9 (Step 1; MS m/z: 300 (M+1) and Example 10 (Step2, acid, MS m/z: 286 (M+1)), and Example 1. MS m/z: 662 (M+1).

Example 23

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-OXO-5-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridine-3-carboxamideStep 1: Tributyl(5,6-dihydro-4H-pyran-2-yl)stannane

A mixture of 3,4-dihydro-2H-pyran (500 mg, 5.94 mmol) in THF (10 mL) wasbrought to −78° C. followed by the addition of tert-butyllithium (12.2mL, 20.8 mmol, 1.7 M in pentane). The resulting yellow solution wasbrought to 0° C. and stirred for 15 min. The reaction was then cooled to−78° C. and tributyltin chloride (4.8 mL, 17.8 mmol) was slowly added.The reaction was monitored by TLC. Upon completion by TLC, water wasadded (20 mL) to the reaction. The organic phase was separated, washedwith water, dried over MgSO₄, concentrated and chromatographed on silicagel using hexanes (500 ml hexanes and 0.5 mL triethylamine). The titlecompound was obtained as a colorless oil. MS m/z: 375 (M+1).

Step 2: Methyl1-cyclopentyl-5-(5,6-dihydro-4H-pyran-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate

The title compound was obtained, as a light yellow oil, using aprocedure analogous to that described in Example 5. MS m/z: 304 (M+1).

Step 3: Methyl1-cyclopentyl-6-oxo-5-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridine-3-carboxylate

The title compound was obtained using a procedure analogous to thatdescribed in Example 2. MS m/z: 306 (M+1).

Step 4:1-cyclopentyl-6-oxo-5-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridine-3-carboxylicacid

The title compound, a white solid, was obtained using a procedureanalogous to that described in Example 10. MS m/z: 292 (M+1).

Step 5:1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-OXO-5-(tetrahydro-2H-pyran-2-yl)-1,6-dihydropyridine-3-carboxamide

The title compound was obtained using a procedure analogous to thatdescribed in Example 1. MS m/z: 668 (M+1).

Example 24

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-6-OXO-5-(tetrahydrofuran-2-yl)-1,6-dihydropyridine-3-carboxamide

The title compound was obtained using a procedure analogous to thatdescribed in Example 23. MS m/z: 654 (M+1).

Example 25

N-((2S,3R)-4-(6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-5-(isopropylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamideStep 1: Methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

A mixture of methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (1.5g, 6.5 mmol) and potassium carbonate (0.99 g, 7.15 mmol) in DMF (25 mL)was stirred at room temperature for 15 min followed by the addition ofmethyl iodide (0.42 mL, 6.83 mmol). The resulting suspension was stirredat room temperature for 17 h. The mixture was partitioned betweenethylacetate and water. The organic phase was separated and the aqueousphase was extracted with ethylacetate. The organic extracts werecombined, washed with brine, dried over MgSO₄ and concentrated to affordthe title compound as a light yellow solid. MS m/z: 246 (M+1).

Step 2: Methyl5-(isopropylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

The title compound, a light yellow oil, was obtained using a procedureanalogous to that described in Example 17. MS m/z: 225 (M+1).

Step 3:5-(isopropylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

The title compound was obtained as a light yellow oil, using a procedureanalogous to that described in Example 10. MS m/z: 211 (M+1).

Step 4:N-((2S,3R)-4-(6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-5-(isopropylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained as a yellow solid, using a procedureanalogous to that described in Example 1. MS m/z: 573 (M+1).

Example 26

N-((2S,3R)-4-(6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-5-(isopropylamino)-1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained as an off-white solid, using a procedureanalogous to that described in Example 25. MS m/z: 587 (M+1)

Example 27

N-((2S,3R)-4-(6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-1-isopropyl-5-(isopropylamino)-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained as a yellow solid, using a procedureanalogous to that described in Example 25. MS m/z: 573 (M+1).

Example 28

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-5-(methylamino)-6-oxo-1,6-dihydropyridine-3-carboxamideStep 1: Methyl5-((4-methoxybenzyl)(methyl)amino)-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate

The title compound was obtained as a colorless oil, using a procedureanalogous to that described in Example 17, with methyl5-bromo-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate (200 mg,0.67 mmol) and (4-methoxyphenyl)-N-methylmethanamine (130 mg, 0.87mmol). MS m/z: 371 (M+1).

Step 2:Methyl-1-cyclopentyl-5-(methylamino)-6-oxo-1,6-dihydropyridine-3-carboxylate

The title compound was obtained as a colorless oil, using a procedureanalogous to that described in Example 2, with methyl5-((4-methoxybenzyl)(methyl)amino)-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate(30 mg, 0.081 mmol). MS m/z: 251 (M+1).

Step 3:1-cyclopentyl-5-(methylamino)-6-oxo-1,6-dihydropyridine-3-carboxylicacid

The title compound was obtained as a light yellow solid, using aprocedure analogous to that described in Example 10. MS m/z: 237 (M+1).

Step 4:1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydrodroxy-1-phenylbutan-2-yl)-5-(methylamino)-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained as a light yellow solid, using aprocedure analogous to that described in Example 1. MS m/z: 599 (M+1).

Example 29

4-Benzyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2-carboxamide

Racemic 4-benzylmorpholine-2-carboxylic acid (16 mg) was dissolved inDMF (0.5 mL) in a reaction flask (1) and DIPEA (0.1 mL) and HATU (42 mg,0.11 mmol) were added. In a separate flask (2) was placed(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-ol,bis HCl salt (35 mg, 0.075 mmol), DIPEA (0.1 mL) and DMF (0.5 mL) andthe reaction was allowed to stir for 10 min before the solution wasadded to flask (1). The reaction in flask (1) was allowed to stir for 1h and then diluted with MeOH (2.0 mL), filtered. The filtrate wasinjected directly onto a reverse phase HPLC purification (80 mL/min on a30.0×150.0 mm C-18(2) Luna Phenomonex column, 10% CH3CN gradient to 100%over 30 min). The pure fractions were evaporated to give the titlecompound. MS m/z: 598 (M+1).

Example 30

1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxopiperidine-3-carboxamide

Methyl 6-oxo-6H-pyran-3-carboxylate (Aldrich, 4.00 g, 26.0 mmol) wasplaced in a 500 mL rbf before 1,4-dioxane (40.0 mL) was added viasyringe. After 5 min, cyclopentyl amine (13.0 mL) was added via syringeand the reaction was allowed to stir for 14 h before the volatiles wereremoved by rotary evaporation. The solid residue was dissolved indiethyl ether (100 mL) and then washed with HCl (10%, 1×100 mL), NaHCO₃(sat, 1×100 mL), brine (sat 100 mL), and dried with magnesium sulfate.The dried solution was filtered and concentrated to provide 4.95 g ofcrude oil which was purified by a 120 g normal phase Isco columnchromatography (50% EtOAc-100% EtOAc in hexanes) to give 2.38 g ofmethyl 1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylate. MS m/z:222 (M+1). This methyl ester was dissolved in THF (30 mL) and water wasadded (10 mL) before the addition of LiOH monohydrate (1.20 g) and thenreaction was placed in a 70° C. oil bath for 2 h. The reaction wascooled and the bulk of the THF was removed by rotary evaporation. Thereaction was then poured into a separatory funnel and HCl (10%, 75 mL)was added before extracting with diethyl ether (3×100 mL). The combinedorganics were washed with brine (sat, 200 mL) and dried with magnesiumsulfate. The solution was filtered and concentrated to provide an offwhite solid (920 mg). MS m/z: 208 (M+1).

This acid was dissolved in MeOH (25 mL) and HOAc was added (2.0 mL)before the addition of PtO₂ (125 mg). A balloon of H₂ was bubbledthrough the reaction and then it was stirred for 12 h under 1 atm of H₂.LC/MS analysis showed that about 50% of the material was reduced. Anadditional portion of PtO₂ was added (125 mg) and the reaction wasrecharged with H₂ and stirred for another 12 h and then filtered througha plug of Celite®. LC/MS showed that the reduction had not progressedany further. The filtrate was concentrated and then dissolved in MeOH(10 mL) and loaded directly to Varian reverse phase HPLC. Thechromatography did not provide clean separation of material. Thefractions were combined in a 500 mL rbf and the CH₃CN was removed byrotary evaporation. The water was frozen and then removed bylypholization to provide 510 mg of a white solid that was used in thenext reaction without further purification.

The crude 1-cyclopentyl-6-oxopiperidine-3-carboxylic acid (35 mg) fromthe above procedure and(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-4-phenylbutan-2-olbis hydrochloride salt (30 mg) were dissolved in DMF (0.7 mL) before theaddition of DIPEA (0.2 mL) and HATU (40 mg) in one portion. The reactionwas allowed to stir overnight and then diluted with MeOH (3 mL) andloaded directly to reverse phase HPLC. The pure fractions wereevaporated to provide the title compound as a mixture of twodiastereomers. MS m/z: 574 (M+1).

Example 31

1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)piperidine-3-carboxamide

1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (Aldrich, 2.20 g,9.60 mmol) was dissolved in DCM (40 mL) in a round bottom flask (rbf),which was placed in a 0° C. bath. Triethyl amine (1.7 mL) was added tothe reaction via syringe and then benzyl chloroformate (1.4 mL) wasadded dropwise via a syringe. The reaction was allowed to stir for 10min and then DMAP (117 mg) was added in on portion. The reaction wasallowed to stir for 1 h and then quenched by pouring into NaHCO₃ (sat,50 mL). The reaction was extracted with DCM (3×50 mL), washed with brine(sat, 200 mL), and dried with sodium sulfate. The solution was filteredand concentrated to provide the benzyl ester as colorless oil that wastaken on to the next step without any further purification. MS m/z: 320(M+1).

The benzyl ester was dissolved in DCM (10 mL) and the rbf was placed ina 0° C. bath. After stirring for 5 min, TFA (8 mL) was added and thereaction was allowed to stir for 2 h and then concentrated on a rotaryevaporator before being placed on high vacuum for 12 h. The crude oilwas poured into Na₂CO₃ (10%, 100 mL) and extracted with DCM (3×75 mL),washed with brine (sat, 200 mL), dried with sodium sulfate, filtered andconcentrated to provide the benzyl piperidine-3-carboxylate as an oilthat was taken on to the next step without any further purification. MSm/z: 220 (M+1).

The crude amine from the above step was dissolved in 1,2-dichloroethane(15 mL) and cyclopentanone (1.0 mL) was added via syringe. The reactionwas allowed to stir for 5 min before the addition of HOAc (0.6 mL) andNaBH(OAc)₃ (2.3 g, 10.9 mmol) in one portion. The reaction was allowedto stir for 48 h and then quenched with Na₂CO₃ (10%, 20 mL) and thereaction was allowed to stir for 1 h before being extracted with DCM(3×50 mL). The combined organics were washed with brine (sat, 200 mL),dried with sodium sulfate, filtered, concentrated to provide 1.3 g ofcrude oil that was purified by a 120 g Isco normal phase column (100%EtOAc) to give benzyl 1-cyclopentylpiperidine-3-carboxylate as acolorless oil. MS m/z: 288 (M+1).

A portion of the benzyl ester from above (164 mg) was dissolved in EtOAc(20 mL) and Pd/C was added (40 mg). One balloon of H₂ was bubbledthrough the reaction and then it was allowed to stir for overnight under1 atm of H₂. The reaction was filtered through a plug of celite and thefiltrate was concentrated to provide the acid as an off white solid. MSm/z: 198 (M+1).

The carboxylic acid (20 mg) was dissolved in DMF (0.5 mL) and then DIPEA(0.1 mL) and HATU (42 mg, 0.11 mmol) were added to the reaction flask.In a separate flask was placed(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-ol,bis HCl salt (40 mg, 0.085 mmol), DIPEA (0.1 mL) and DMF (0.5 mL) andthe reaction was allowed to stir for 10 min before the solution wasadded to the acid/HATU mixture. The reaction was allowed to stir for 1 hand then loaded directly onto a reverse phase HPLC. The pure fractionswere concentrated to provide the title compound as a mixture of twodiastereomers. MS m/z: 574.8 (M+1).

Example 32

N-((2S,3R)-3-hydroxy-4-((S)-6-isopropyl-2,2-spirocyclopentylchroman-4-ylamino)-1-phenylbutan-2-yl)-1-(pyridin-2-yl)piperidine-3-carboxamide

Pure benzyl piperidine-3-carboxylate (170 mg, 0.776 mmol; Example 31)was placed in a microwave tube. DIPEA (0.50 mL), tert-BuOH (1.5 mL) and2-fluoropyridine (Aldrich, 0.40 mL) were added to the tube via syringesbefore the tube was subjected to microwave irradiation at 180° C. for 20min. LC/MS showed partial conversion to the desired pyridine derivative.The tube was subjected to further microwave irradiation at 220° C. for20 min and then it was allowed to cool to room temperature. Thevolatiles were removed by rotary evaporation to provide 229 mg of crudeoil which was dissolved in MeOH (8.0 mL) and then subjected to reversephase HPLC. The pure fractions were poured into Na₂CO₃ (10%, 75 mL) andextracted with EtOAc (3×50 mL), washed with brine (sat, 150 mL), driedwith sodium sulfate, filtered and concentrated to provide 90 mg ofbenzyl 1-(pyridin-2-yl)piperidine-3-carboxylate. MS m/z: 297 (M+1)

The benzyl ester from above was dissolved in EtOAc (30 mL) and 10% Pd/C(20 mg) was added in one portion. A balloon of H₂ was bubbled throughthe reaction before it was allowed to stir under 1 atm of H₂ for 48 h.The reaction was filtered through a plug of celite and concentrated toprovide 58 mg of clean 1-(pyridin-2-yl)piperidine-3-carboxylic acid. MSm/z: 207 (M+1)

The 1-(pyridin-2-yl)piperidine-3-carboxylic acid was dissolved in DMF(1.0 mL) before DIPEA (0.1 mL),(2R,3S)-3-amino-1-((S)-6-isopropyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-ol,bis hydrochloride salt (58 mg), and HATU (50 mg) were added to thereaction. The reaction was allowed to stir for 1 h and then loadeddirectly to reverse phase HPLC. The pure fractions were poured intoNa₂CO₃ (10%, 100 mL) and extracted with EtOAc (3×75 mL). The combinedorganics were washed with brine (sat 100 mL) and dried with sodiumsulfate. The solution was filtered and concentrated to provide the titlecompound. MS m/z: 597.4 (M+1)

Example 33

N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-oxoimidazolidine-4-carboxamide

To a 25 mL RBF containing(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-4-phenylbutan-2-olbis hydrochloride salt (25 mg, 55 μmol) and2-oxoimidazolidine-4-carboxylic acid (Aldrich, 7.2 mg, 55 μmol) wasadded DMF (1 mL) and N-ethyl-N-isopropylpropan-2-amine (7.1 mg, 55 μmol)and the mixture was allowed to stir at 23° C. for 5 min. HATU (21 mg, 55μmol) was added in one portion and the reaction was allowed to stir for12 h, while monitoring by LC/MS. The crude reaction was quenched withMeOH (2.0 mL) and then loaded directly to reverse phase HPLC, the purefractions were concentrated in a Genevac lyophilizer to provide the TFAsalt of the title compound as a white solid. MS m/z: 494 (M+1).

Example 34

1-acetyl-5-(cyclohexylmethyl)-N-((2S,3R)-4-(2-spirocyclobutyl-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)piperidine

The title compound may be obtained using a procedure analogous to thatdescribed immediately below, to synthesize1-acetyl-5-(cyclohexylmethyl)-N-((2S,3R)-4-(6-ethylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)piperidine.

Step 1: Ethyl-5-benzylnicotinate

A suspension of Zn (1.0 g, 15 mmol) and I₂ (130 mg, 0.5 mmol) in DMA (15mL) was stirred vigorously until the red color dissipated (3-5 min).Benzyl bromide (1.7 g, 10 mmol) was introduced and the resulting slurrywas heated at 80° C. for 2.5 h at which point Cl₂Pd(PPh₃)₂ (250 mg, 0.35mmol) and a solution of ethyl-5-bromonicotinate (1.1 g, 5.0 mmol) inbenzene (10 mL) were introduced and the reaction was heated at 80° C.for 1 h. The reaction was allowed to cool to room temperature and wasdiluted with EtOAc (100 mL). The mixture was poured into NaHCO₃ (5%aqueous, 100 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (2×50 mL). The combined organic layers weresequentially washed with H₂O (3×100 mL) and brine before being driedover Na₂SO₄. Concentration and purification by silica gel chromatography(hexane→50% EtOAc/hexane) provided the title compound as a brown oil. MSm/z: 242.1 (M+1).

Step 2: Ethyl 5-(cyclohexylmethyl)piperidine-3-carboxylate

A suspension of ethyl-5-benzylnicotinate (1.0 g, 4.1 mmol) and PtO₂ (800mg) in EtOH (25 mL) and HCl (conc., 5.0 mL) was mixed in a Parr shakerunder 40 psi of H₂ for 2 hours. The mixture was filtered through celiteand concentrated to about 10% of the original volume. The resultingmixture was extracted with CH₂Cl₂ (3×30 mL). The organic layer wasconcentrated under reduced pressure to furnish the title compound (755mg, 73% yield) as a white solid. MS m/z: 254.3 (M+1).

Step 3: ethyl 1-acetyl-5-(cyclohexylmethyl)piperidine-3-carboxylate

Triethylamine (410 μL, 2.9 mmol) was added to a solution of ethyl5-(cyclohexylmethyl)piperidine-3-carboxylate (180 mg, 0.71 mmol) andacetyl chloride (120 mg, 1.4 mmol) in CH₂Cl₂ (10 mL). The reaction wasmaintained at room temperature for 30 min before being diluted withCH₂Cl₂ (20 mL) and poured into HCl (1 N, 20 mL). The layers wereseparated and the aqueous layer was extracted with CH₂Cl₂ (3×20 mL). Thecombined organic layers were sequentially washed with H₂O (10 mL) andbrine before being dried over Na₂SO₄. Concentration under reducedpressure and purification by silica gel chromatography (hexane→80%EtOAc/hexane) provided the title compound as a yellow oil. MS m/z: 296.1(M+1).

Step 4: 1-acetyl-5-(cyclohexylmethyl)piperidine-3-carboxylic acid

LiOH (2 N, 500 μL) was added to a solution of ethyl1-acetyl-5-(cyclohexylmethyl)piperidine-3-carboxylate (180 mL, 0.61mmol) in MeOH (1 mL) and THF (5 mL). After being maintained for twohours, the reaction was poured into a mixture of CH₂Cl₂ (25 mL) and H₂O(10 mL). The layers were separated and the aqueous layer was extractedwith CH₂Cl₂ (10 mL). The aqueous layer was acidified to pH 1 with 1N HCland extracted with CH₂Cl₂ (3×20 mL). The combined organic layers weresequentially washed with H₂O (10 mL) and brine before being dried overNa₂SO₄. Concentration under reduced pressure provided the title compoundas a colorless oil. MS m/z: 268.0 (M+1).

Step 5:1-acetyl-5-(cyclohexylmethyl)-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)piperidine

1-acetyl-5-(cyclohexylmethyl)piperidine-3-carboxylic acid (25 mg, 0.09mmol),(2R,3S)-3-amino-1-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-ol.2HCl (40 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) were combined in a 5mL round bottom flask. CH₂Cl₂ (1 mL) and DIPEA (65 μL, 0.37 mmol) wereintroduced and the resulting solution was stirred overnight. Thereaction was diluted with EtOAc (10 mL) and poured in 10% aqueous K₂CO₃(10 mL). The layers were separated and the aqueous layer was extractedwith CH₂Cl₂ (3×30 mL). The combined organic layers were sequentiallywashed with H₂O (10 mL) and brine before being dried over Na₂SO₄. Thederived residue was purified by HPLC (Shimadzu, 15-85% MeCN) to providethe title compound as a white solid. MS m/z: 644.3 (M+1).

Example 35

1-methylsulfonyl-5-(cyclohexylmethyl)-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)piperidineStep 1: Ethyl5-(cyclohexylmethyl)-1-(methylsulfonyl)piperidine-3-carboxylate

Triethylamine (340 mL, 2.4 mmol) was added to a solution of ethyl5-(cyclohexylmethyl)piperidine-3-carboxylate (155 mg, 0.60 mmol) andmethanesulfonyl chloride (75 mL, 0.90 mmol) in CH₂Cl₂ (6 mL) cooled to0° C. The reaction was maintained at this temperature for 15 min atwhich point the whole was allowed to warm to RT and stir for anadditional 3 h. The reaction was diluted with CH₂Cl₂ (20 mL) and pouredinto HCl (1N, 20 mL). The layers were separated and the aqueous layerwas extracted with CH₂Cl₂ (3×20 mL). The combined organic layers weresequentially washed with H₂O (10 mL) and brine before being dried overNa₂SO₄. Concentration under reduced pressure provided the titlecompound. MS m/z: 332.1 (M+1).

Step 2: 5-(cyclohexylmethyl)-1-(methylsulfonyl)piperidine-3-carboxylicacid

The title compound was prepared using a procedure analogous to thatdescribed in Step 4 of Example 34. MS m/z: 304.0 (M+1).

Step 3:1-methylsulfonyl-5-(cyclohexylmethyl)-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)piperidine

The title compound was prepared using a procedure analogous to thatdescribed in Step 5 of Example 34. MS m/z: 680.3 (M+1).

Example 36

N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)cyclobutanecarboxamide

(S)-6-Ethyl-2,2-spirocyclobutylchroman-4-amine 2 HCl (50 mg, 0.11 mmol),cyclobutyl carboxylic acid (11 mg, 0.11 mmol) and HATU (43 mg, 0.11mmol) were combined in a 1 gram vial. DMF (1.5 mL) was introduced andthe resulting solution was treated with DIPEA (100 mL, 0.56 mmol). Thereaction was stirred for 1 hour before being quenched with HCl (6 N,˜100 mL). The mixture was purified by HPLC (Shimadzu, 15-85%) to providethe title compound as a white solid. MS m/z: 463.1 (M+1).

Example 37

N-((2S,3R)-4-((8)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)cyclopentanecarboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 36. MS m/z: 477.2 (M+1).

Example 38

2-ethoxy-N-((2S,3R)-4-((8)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)butanamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 36. MS m/z: 495.3 (M+1)

Example 39

N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-tetrahydrofuran-3-carboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 36. MS m/z: 495.4 (M+1).

Example 40

2-(2-Bromo-5-fluorophenyl)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)cyclopropanecarboxamideStep 1: (E)-3-(2-Bromo-5-fluorophenyl)-N-methoxy-N-methylacrylamide

Oxalyl chloride (2.0 M in dichloromethane, 2.08 mL, 4.16 mmol) was addedto a suspension of (E)-3-(2-bromo-5-fluorophenyl)acrylic acid (678 mg,2.77 mmol) in dichloromethane (8 mL). N,N-dimethylformamide (11 L, 0.14mmol) was added, and the resulting mixture was stirred at 25° C. for 1h. The reaction mixture was concentrated in vacuo, and4-dimethylaminopyridine (3 mg, 0.025 mmol), N,O-dimethylhydroxylaminehydrochloride (270 mg, 2.77 mmol), Hunig's base (1.44 mL, 8.28 mmol),and dichloromethane (8 ml) were added. The mixture was stirred at 25° C.for 10 h, then transferred to a separatory funnel with dichloromethane(100 mL), and the organic layer was extracted sequentially with water (7mL), 0.5 M sodium carbonate (7 mL), 1 M hydrochloric acid (7 mL), andhalf-saturated brine (7 mL), and then dried over sodium sulfate andconcentrated. Purification of the concentrate by flash columnchromatography (33% to 40% EtOAc/hexane) afforded the title compound asa white solid. MS m/z: 288 & 290 (M+1).

Step 2:2-(2-Bromo-5-fluorophenyl)-N-methoxy-N-methylcyclopropane-carboxamide

Sodium hydride (60%, 122 mg, 3.05 mmol, Aldrich) was added to asuspension of trimethylsulfoxonium iodide (671 mg, 3.05 mmol, Aldrich)in DMSO (6 mL). The mixture was stirred at 25° C. for 30 min, and(E)-3-(2-bromo-5-fluorophenyl)-N-methoxy-N-methylacrylamide was added asa solution in DMSO (3 mL). The mixture was stirred at 25° C. for 12 h,then transferred to a separatory funnel with H₂O (40 mL), and the titlecompound was extracted using 75% ether/hexane (3×40 mL). The organiclayer was dried over sodium sulfate and concentrated. Purification byflash column chromatography (33% EtOAc/hexane) afforded the titlecompound as a colorless oil. MS m/z: 302 and 304 (M+1).

Step 3: 2-(2-Bromo-5-fluorophenyl)cyclopropanecarboxylic acid

A solution of2-(2-bromo-5-fluorophenyl)-N-methoxy-N-methylcyclopropane-carboxamide(304 mg, 1.0 mmol), 10 M potassium hydroxide (3.5 mL, 35 mmol), anddioxane (2.5 mL) was heated at 130° C. in a sealed tube for 19 h. Uponcooling to room temperature, the reaction mixture was acidified with 3 MHCl (20 mL), and the product was extracted with 5%methanol/dichloromethane (3×30 mL). The organic fractions were combined,dried over sodium sulfate, and concentrated to afford the title compoundas a white solid. MS m/z: 259 & 261 (M+1).

Step 4: Synthesis of2-(2-Bromo-5-fluorophenyl)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)cyclopropanecarboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 35, wherein2-(2-bromo-5-fluorophenyl)cyclopropanecarboxylic acid (Step 3) wascoupled with(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-olto afford the desired product (1:1 mixture of cyclopropyl epimers) as ayellow film. MS m/z: 635 & 637 (M+1).

Example 41

N-((2S,3R)-4-((S)-6-Ethyl-2-spirocyclobutyl-chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound may be obtained using a procedure analogous to thatdescribed immediately below, used to synthesizeN-((2S,3R)-4-((S)-6-Ethyl-chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide.

Step 1: (±)-Ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

To a solution of ethyl 2,3-dibromopropionate (8.05 g, 31.0 mmol,Aldrich) in acetone (35 mL) was added o-aminophenol (3.38 g. 31.0 mmol)and potassium carbonate (5.1 g, 36.9 mmol). The reaction mixture wasstirred at reflux under a water condenser for 18 h. Upon cooling to roomtemperature, the reaction was concentrated in vacuo, and the residue wastaken up in water (50 mL) and the product was extracted using EtOAc(3×75 mL). The organic fractions were combined, washed with saturatedbrine (15 mL), dried over sodium sulfate, and concentrated. Purificationof the product by flash column chromatography (30% EtOAc/hexane)afforded the title compound as a yellow oil. MS m/z: 208 (M+1).

Step 2: (±)-Lithium 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

A solution of lithium hydroxide monohydrate (1.43 g, 34.2 mmol) in water(50 mL) was added to a solution of ethyl3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (3.55 g, 17.1 mmol) indioxane (50 mL), and the mixture was stirred at 25° C. for 21 h. Thereaction mixture was concentrated to afford the title compound. MS m/z:180 (M+1 of acid).

Step 3:N-((2S,3R)-4-((S)-6-Ethylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 35, wherein (±)-lithium3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate was coupled with(2R,3S)-3-amino-1-((S)-6-ethylchroman-4-ylamino)-4-phenylbutan-2-ol toafford the title compound (a 1:1 mixture of epimers at the benzooxazinestereocenter) as a white solid. MS m/z: 502 (M+1).

Example 42

Synthesis ofN-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamideStep 1: (±)-Ethyl4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

Tris(dibenzylideneacetone)dipalladium (0) (4.3 mg, 0.0046 mmol),xantphos (8.2 mg, 0.014 mmol), and bromobenzene (40 L, 0.381 mmol) wereadded to a solution of (±)-ethyl3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (65 mg, 0.31 mmol) indioxane (2.5 mL). The solids were allowed to dissolve, and cesiumcarbonate (143 mg, 0.44 mmol) was added, and the suspension was stirredat 100° C. for 24 h. The mixture was cooled to ambient temperature,diluted with water (20 mL), and the product was extracted with 67%EtOAc/hexane (3×25 mL). The organic layers were combined, dried oversodium sulfate, and concentrated. Purification of the crude concentrateby flash column chromatography using 15% EtOAc/hexane afforded the titlecompound. MS m/z: 284 (M+1).

Step 2: (±)-Lithium4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

(±)-Ethyl 4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate wasconverted to the title compound using the procedure described in Step 2of Example 41. MS m/z: 256 (M+1 of acid).

Step 3:N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 35, wherein (±)-lithium4-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate was coupledwith(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-olto afford the title compound (as a 1:1 mixture of epimers at thebenzooxazine stereocenter) as a colorless film. MS m/z: 632 (M+1).

Example 43

4-Cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamideStep 1: (±)-Ethyl4-cyclopentyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

Cyclopentanone (83 L, 0.94 mmol), acetic acid (54 L, 0.94 mmol), andmagnesium sulfate (113 mg, 0.94 mmol) were added to a solution of(±)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid (Example 3a,65 mg, 0.31 mmol) in dichloroethane (1.25 mL). Sodiumtriacetoxyborohydride (100 mg, 0.47 mmol) was added, followed bydichloroethane (1.25 mL), and the suspension was stirred at 25° C. for48 h. The reaction mixture was quenched with half-saturated sodiumbicarbonate, and the product was extracted using 67% EtOAc/hexane (3×25mL). The combined organic fractions were dried over sodium sulfate andconcentrated. Purification of the product by flash column chromatography(10% EtOAc/hexane) afforded the title compound as an oil. MS m/z: 276(M+1).

Step 2: (±)-Lithium4-cyclopentyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

(±)-Ethyl4-cyclopentyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate wasconverted to the title product using the procedure described in in step2 of Example 41. MS m/z: 248 (M+1 of acid).

Step 3:4-Cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 35, wherein (±)-lithium4-cyclopentyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate wascoupled with(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-olto afford the title compound (as a 1:1 mixture of epimers at thebenzooxazine stereocenter) as a white solid. MS m/z: 624 (M+1).

Example 44

(R)—N-((2S,3R)-4-((S)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1,2,3,4-tetrahydroquinoline-3-carboxamideStep 1: Potassium quinoline-3-carboxylate

In a sealable tube, quinoline-3-carbonitrile (308 mg, 2.0 mmol) wassuspended in 1 M potassium hydroxide (3 mL), and the reaction vessel wassealed and heated at 120° C. for 24 h. The mixture was cooled to ambienttemperature, and concentrated. The crude material was used directly inthe next step. MS m/z: 174 (M+1 of acid).

Step 2: Ethyl quinoline-3-carboxylate

In a sealable tube, concentrated sulfuric acid (32 L) was added to asolution of potassium quinoline-3-carboxylate in ethanol (1 mL). Theflask was sealed and heated at 85° C. for 24 h. The mixture was cooledto ambient temperature, basified with 1 M sodium carbonate (10 mL), andthe product was extracted with dichloromethane (3×15 mL). The organicfractions were dried over sodium sulfate and concentrated. Purificationof the product by flash column chromatography (10% to 20% EtOAc/hexane)afforded the title compound (292 mg, 1.45 mmol). MS m/z: 202 (M+1).

Step 3: (±)-Ethyl 1,2,3,4-tetrahydroquinoline-3-carboxylate

Borane-pyridine complex (8 M, 292 mL, 2.34 mmol) was added to a solutionof Ethyl quinoline-3-carboxylate (235 mg, 1.17 mmol) in acetic acid (10mL). The solution was stirred at 25° C. for 20 h. The reaction mixturewas concentrated in vacuo, basified with 1 M sodium carbonate (30 mL),and the product was extracted with dichloromethane (3×35 mL). Theorganic layers were dried over sodium sulfate and concentrated.Purification of the product by flash column chromatography (10% to 20%EtOAc/hexane) afforded the title compound (239 mg, 1.15 mmol). MS m/z:206 (M+1).

Step 4: (±)-Lithium 1,2,3,4-tetrahydroquinoline-3-carboxylate

(±)-Ethyl 1,2,3,4-tetrahydroquinoline-3-carboxylate was converted to thetitle product using the general procedure described in step 2 of Example41. MS m/z: 178 (M+1 of acid).

Step 5:(R)—N-((2S,3R)-4-((S)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1,2,3,4-tetrahydroquinoline-3-carboxamide

The title compound, an off-white solid, was prepared using a procedureanalogous to that described in Example 35. MS m/z: 554 (M+1).

Example 45

(S)—N-((2S,3R)-4-((S)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamideStep 1: (±)-Ethyl4-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

In a sealable tube, tris(dibenzylideneacetone) dipalladium (0) (5.2 mg,0.0056 mmol), (S)-BINAP (10.7 mg, 0.017 mmol), cesium carbonate (132 mg,0.41 mmol), 2-bromopyridine (33 L, 0.35 mmol), and ethyl3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (Example 3a, 60 mg,0.29 mmol) were dissolved in dioxane (2 mL). The reaction vessel wassealed and the suspension was heated at 100° C. for 20 h. The reactionmixture was cooled to ambient temperature, diluted with water (15 mL),and the product was extracted with dichloromethane (3×20 mL). Theorganic fractions were dried over sodium sulfate and concentrated.Purification of the product by flash column chromatography (15% to 25%EtOAc/hexane) afforded the title compound (46 mg, 0.16 mmol). MS m/z:285 (M+1).

Step 2: (±)-Lithium4-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

(±)-Ethyl4-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate wasconverted to the title compound using the general procedure described inExample 41. MS m/z: 257 (M+1 of acid).

Step 3:(S)—N-((2S,3R)-4-((S)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 42, and obtained as a white solid. MS m/z: 633(M+1).

Example 46

(R)—N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-(pyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was isolated, from the same crude reaction mixture ofStep 3 in Example 45, as a white solid. MS m/z: 633 (M+1).

Example 47

(R)—N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamideStep 1: (±)-Ethyl4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

In a sealable vessel, potassium carbonate (56 mg, 0.41 mmol) was addedto a solution of (±)-ethyl3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (60 mg, 0.29 mmol) andiodomethane (22 L, 0.35 mmol) in acetone (2 mL). The vessel was sealedand the reaction mixture was stirred at 60° C. for 24 h. The mixture wascooled to ambient temperature, diluted with dichloromethane (60 mL), andthe organic layer was extracted with water (10 mL) and half-saturatedbrine (10 mL). The organic layer was dried over sodium sulfate andconcentrated. Purification of the concentrate by flash columnchromatography (5% to 10% EtOAc/hexane) afforded the title compound (43mg, 0.19 mmol). MS m/z: 222 (M+1).

Step 2: (±)-Lithium4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

(±)-Ethyl 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate wasconverted to the title compound using the general procedure described inExample 41. MS m/z: 194 (M+1 of acid).

Step 3:(R)—N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 42 and obtained as a white solid. MS m/z: 570(M+1).

Example 48

(S)—N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was isolated from the same crude reaction mixturedescribed in Step 3 of Example 47, as a white solid. MS m/z: 570 (M+1).

Example 49

N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-methyl-1,2,3,4-tetrahydroquinoline-3-carboxamide

The title compound was obtained, as a 1:1 mixture of epimers at thetetrahydroquinoline stereocenter, as a white solid, in a manneranalogous to the general procedure described in Example 47. MS m/z: 568(M+1).

Example 50

(R)-4-acetyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamideStep 1: (±)-Ethyl4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

Acetyl chloride (23 L, 0.33 mmol) was added to a solution of (±)-ethyl3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (Example 3a, 55 mg,0.27 mmol), DMAP (1.6 mg, 0.013 mmol), and Hunig's base (63 L, 0.36mmol) in dichloromethane (2 mL). The solution was stirred at 25° C. for24 h, then the reaction mixture was diluted with dichloromethane (60 mL)and the mixture was extracted with 0.1 M sodium carbonate (7 mL) andhalf-saturated brine (7 mL). The organic layer was dried over sodiumsulfate and concentrated. Purification of the product by flash columnchromatography (40% EtOAc/hexane) afforded the title compound (46 mg,0.18 mmol). MS m/z: 250 (M+1).

Step 2: (±)-Lithium4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

(±)-Ethyl 4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate wasconverted to the title compound using the general procedure described inExample 41. MS m/z: 222 (M+1 of acid).

Step 3:(R)-4-Acetyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound, a white solid, was prepared using a procedureanalogous to that described in Example 42. MS m/z: 598 (M+1).

Example 51

(S)-4-acetyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was prepared in a manner analogous to that describedin Example 50, and obtained as a white solid. MS m/z: 598 (M+1).

Example 52

(R)-tert-Butyl2-(((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxylateStep 1: (±)-4-tert-Butyl 2-ethyl2,3-dihydrobenzo[b][1,4]oxazine-2,4-dicarboxylate

DMAP (3.2 mg, 0.026 mmol), Hunig's base (150 L, 0.86 mmol), and Boc₂O(154 mg, 0.70 mmol) were added to a solution of (±)-Ethyl3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (112 mg, 0.54 mmol) indichloromethane (4 mL). The solution was stirred at 25° C. for 24 h. Thereaction mixture was dissolved in dichloromethane (60 mL), and theorganic layer was extracted with 0.5 M sodium carbonate (7 mL) andhalf-saturated brine (7 mL), dried over sodium sulfate, andconcentrated. Purification of the product by flash column chromatography(10% to 20% EtOAc/hexane) afforded the title compound (31 mg, 0.10mmol). MS m/z: 252 (M+1 of carbamic acid).

Step 2: (±)-Lithium4-(tert-butoxycarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

(±)-4-tert-Butyl 2-ethyl2,3-dihydrobenzo[b][1,4]oxazine-2,4-dicarboxylate was converted to thetitle compound using the general procedure described in Example 41. MSm/z: 224 (M+1 of carbamic acid).

Step 3: (R)-tert-butyl2-(((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxylate

The title compound, a white solid, was prepared using a procedureanalogous to that described in Example 42. MS m/z: 656 (M+1).

Example 53

(S)-tert-butyl2-(((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)-2,3-dihydrobenzo[b][1,4]oxazine-4-carboxylate

The title compound was isolated from the same reaction mixture describedin Example 52, as a white solid. MS m/z: 656 (M+1).

Example 54

6-bromo-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 42, and was obtained as a 1:1 mixture of epimers atthe benzooxazine stereocenter, as a white solid. MS m/z: 634 & 636(M+1).

Example 55

N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 42, yielding the title compound as a 1:1 mixture ofepimers at the benzooxazine stereocenter, as a white solid. MS m/z: 574(M+1).

Example 56

(R)-4-benzoyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound, a white solid, was prepared using a procedureanalogous to that described in Example 42. MS m/z: 660 (M+1).

Example 57

(S)-4-benzoyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was isolated from the same reaction mixture describedin Example 56, as a white solid. MS m/z: 660 (M+1).

Example 58

(R)-6-Bromo-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide(1127042) Step 1: (±)-Ethyl6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

2-Amino-4-bromophenol was converted to the title compound using theprocedure described in Example 41. MS m/z: 286 & 288 (M+1).

Step 2: (±)-Ethyl6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

(±)-Ethyl 6-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate wasconverted to the title compound using the general procedure described inExample 41. MS m/z: 300 & 302 (M+1).

Step 3: (±)-Lithium6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

(±)-Ethyl6-bromo-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate wasconverted to the title compound using the general procedure described inExample 41. MS m/z: 272 & 274 (M+1 of acid).

Step 4:(R)-6-Bromo-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound, a white solid, was prepared using a procedureanalogous to that described in Example 35. MS m/z: 648 & 650 (M+1).

Example 59

(S)-6-Bromo-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide(1127187)

The title compound was isolated from the same reaction mixture describedin Example 58, as a white solid. MS m/z: 648 & 650 (M+1).

Example 60

(S)—N-((2S,3R)-4-((S)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 35, and was obtained as a 1:1 mixture of epimers atthe benzooxazine stereocenter, as a white solid. MS m/z: 556 (M+1).

Example 61

(S)—N-((2S,3R)-4-((S)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound, a white solid, was obtained using the same generalprocedure described in Examples 41 and 55, as a 1:1 mixture of epimersat the benzooxazine ring. MS m/z: 588 (M+1).

Example 62

(R)-4-Acetyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamideStep 1: (±)-Ethyl7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

2-Amino-5-fluorophenol was converted to the title compound using thegeneral procedure described in Example 41. MS m/z: 226 (M+1).

Step 2: (±)-Ethyl4-acetyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

(±)-Ethyl 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate wasconverted to the title compound using the general procedure described inExample 47. MS m/z: 268 (M+1).

Step 3: (±)-Lithium4-acetyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

(±)-Ethyl4-acetyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate wasconverted to the title compound using the general procedure described inExample 41. MS m/z: 240 (M+1 of acid).

Step 4:(R)-4-acetyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound was prepared using a procedure analogous to thatdescribed in Example 34, and obtained as a white solid. MS m/z: 616(M+1).

Example 63

N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide

The title compound, a white solid, was prepared using a procedureanalogous to that described in Example 62, and obtained as a 1:1 mixtureof epimers at the benzooxazine stereocenter. MS m/z: 574 (M+1).

The following compounds in Tables 1 and 2 (Examples 64-104) and thespecific Examples described thereafter are additional representativeexamples of Formulas I-III, as provided by the present invention.

TABLE 1

R³ Ex. and No. R¹ B R⁴ X¹ S 64 1-morpholinyl phenyl-O—CH₂— H NHcyclobutyl 65 1-piperazinyl phenyl-S—CH₂— H S cyclobutyl 661-piperidinyl phenyl-NH—CH₂— H O cyclobutyl 67 3-oxo-1- phenyl-CH₂— H NHcyclopentyl pyrrolidinyl 68 1-morpholinyl phenyl-O—CH₂— H S cyclopentyl69 1-piperazinyl phenyl-S—CH₂— H O cyclopentyl 70 oxo-pyrrolidinylphenyl-NH—CH₂— H SO₂ cyclopropyl 71 oxazolidinyl phenyl-CH₂— H NHcyclopropyl 72 isoxazolidinyl phenyl-O—CH₂— H S cyclopropyl 73 indolinylphenyl-S—CH₂— H O cyclohexyl 74 1-morpholinyl phenyl-NH—CH₂— H SO₂cyclohexyl 75 1-piperazinyl phenyl-CH₂— H NH cyclohexyl 76 1-piperidinylphenyl-O—CH₂— H S cyclobutyl 77 3-oxo-1- phenyl-S—CH₂— H O cyclobutylpyrrolidinyl 78 1-morpholinyl phenyl-NH—CH₂— H SO₂ cyclobutyl 791-piperazinyl phenyl-CH₂— H NH cyclopentyl 80 oxo-pyrrolidinylphenyl-O—CH₂— H S cyclopentyl 81 oxazolidinyl phenyl-S—CH₂— H Ocyclopentyl 82 isoxazolidinyl phenyl-NH—CH₂— H SO₂ cyclohexyl 83indolinyl phenyl-CH₂— H NH cyclohexyl 84 1-morpholinyl phenyl-O—CH₂— H Scyclohexyl

TABLE 2

R³ Ex. and No. R¹ B R⁴ X¹ S 85 1-morpholinyl 4-CH₃-phenyl H NHcyclobutyl 86 1-piperazinyl 4-CH₃-phenyl H S cyclobutyl 87 1-piperidinyl4-CH₃-pyridyl H O cyclobutyl 88 3-oxo-1-pyrrolidinyl 4-CH₃-phenyl H NHcyclopentyl 89 1-morpholinyl 3-CH₃-phenyl H S cyclopentyl 901-piperazinyl 3-CH₃-phenyl H O cyclopentyl 91 oxo-pyrrolidinyl3-CH₃-phenyl H SO₂ cyclopropyl 92 oxazolidinyl 3-CH₃-phenyl H NHcyclopropyl 93 isoxazolidinyl phenyl H S cyclopropyl 94 indolinyl phenylH O cyclohexyl 95 1-morpholinyl phenyl H SO₂ cyclohexyl 96 1-piperazinylpyridyl H NH cyclohexyl 97 1-piperidinyl phenyl H S cyclobutyl 983-oxo-1-pyrrolidinyl phenyl H O cyclobutyl 99 1-morpholinyl 3-F-phenyl HSO₂ cyclobutyl 100 1-piperazinyl 3-Cl-phenyl H NH cyclopentyl 101oxo-pyrrolidinyl 3-CN-phenyl H S cyclopentyl 102 oxazolidinyl3-NH₂-phenyl H O cyclopentyl 103 isoxazolidinyl 2-F-phenyl H SO₂cyclohexyl 104 indolinyl 4-CH₃-phenyl H NH cyclohexyl

Example 105

1-Cyclopentyl-N((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide.TFAsalt Step 1: 6-Ethyl-2,2-spirocyclopentyl-2,3-dihydrochromen-4-one

A mixture of 2-hydroxyl-5-ethylacetophenone (5.0 g, 30.47 mmol),cyclopentanone (3.30 g, 39.61 mmol), and pyrrolidine (0.54 g, 7.62 mmol)in toluene (70 mL) was heated at reflux with Dean-Stark trap for 24 h.The mixture was cooled, washed with 5 N HCl, brine, dried over MgSO₄,concentrated and purified by ISCO (5% EtOAc/Hexanes) to give the titlecompound as a light yellow oil (5.93 g, 84%).

Step 2: (R)-6-Ethyl-2,2-spirocyclopentylchroman-4-ol

To a stirring, cooled (0° C.) solution of(S)-2-methyl-CBS-oxazaborolidine (1.91 mL, 1.92 mmol, 1M solution intoluene) was separately added a solution of 2 M borane-methyl sulfide(9.60 mL, 19.16 mmol) in toluene (30 mL) and a solution of6-ethyl-2,2-spirocyclopentyl-2,3-dihydrochromen-4-one (4.90 g, 21.29mmol) in toluene (30 mL), over a period of about 1 h. The reactionmixture was stirred for 15 min., quenched with 5 N HCl (60 mL) andstirred for 1 h. The reaction was extracted with ether (3×), washed withbrine, dried over MgSO₄, concentrated and purified by ISCO (20%EtOAc/Hexanes) to give the title compound as a white solid (3.90 g,80%).

Step 3: (S)-4-Azido-6-ethyl-2,2-spirocyclopentylchroman

To a stirred, cooled (0° C.) solution of(R)-6-ethyl-2,2-spirocyclopentylchroman-4-ol (3.90 g, 16.80 mmol) intoluene (40 mL) was added DPPA (5.10 g, 18.48 mmol) drop-wise. After 10min., DBU (2.82 g, 18.48 mmol) was added in 5 min. The reaction mixturewas stirred at RT for 24 h, quenched with H₂O and extracted with ether(3×). The organic extracts were combined, dried over MgSO₄ andconcentrated to give the title compound as a crude brown oil (4.30 g,100%).

Step 4: (S)-6-Ethyl-2,2-spirocyclopentylchroman-4-amine

To a stirring solution of(S)-4-azido-6-ethyl-2,2-spirocyclopentylchroman (5.00 g, 21.44 mmol) inTHF (50 mL) was added PPh₃ (5.30 g, 23.58 mmol). After stirring thereaction at RT for 3 h, H₂O was added. The mixture was stirred for 48 hand heated at reflux for 1 h. The mixture was cooled, 2 N HCl was addeduntil the reaction pH=1. The reaction was extracted with toluene (3×,discarded). The aqueous layer was neutralized, extracted with CH₂Cl₂(3×), dried over Na₂SO₄, and concentrated to give the title compound asa light yellow oil (4.20 g, 93%).

Step 5:(2R,3S)-3-Amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylylamino)-4-phenylbutan-2-oldihydrochloride salt

A mixture of t-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate(4.85 g, 17.31 mmol) and (S)-6-ethyl-2,2-spirocyclopentylchroman-4-amine (4.00 g, 17.31 mmol) in EtOH (60 mL) was heated at 70°C. for 24 h. The mixture was cooled, concentrated, purified bychromatography on an ISCO (40% EtOAc/Hexanes) to give an off-whitesolid. The solid was taken up in p-dioxane (60 mL) to which was added 10mL of 4 M HCl in p-dioxane and the mixture was stirred at RT overnight.The mixture was concentrated to give the title compound as a lightyellow solid (5.30 g, 65%). MS (m/z, M+1):395.3.

Step 6:1-Cyclopentyl-N((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide.TFAsalt

A mixture of 1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxylic acid (0.10 g, 0.33 mmol),(S)-6-ethyl-2,2-spirocyclopentyl chroman-4-amine (0.16 g, 0.40 mmol),HOBt (0.055 g, 0.40 mmol), i-Pr₂Net (0.21 mL, 1.20 mmol), and EDCI (0.08g, 0.40 mmol) in DMF (2 mL) was stirred at RT for 24 h. The mixture wasquenched by H₂O, extracted with CH₂Cl₂ (3×), dried over Na₂SO₄ andconcentrated. The crude concentrate was purified by reverse phase HPLCto give the title compound. MS (m/z, M+1): 667.3.

Example 106

N-((2S,3R)-4-((S)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)3-hydroxy-1-phenylbutan-2-yl)-5-oxo-6-(pyridin-2-yl)-1,2,3,5-tetrahydroindolizine-8-carboxamide.TFAsalt Step 1: 1-(2-Tosylacetyl)pyrrolidin-2-one

To a stirred solution of p-toluenesulfonyl acetic acid (8.4 g, 39.21mmol) in toluene (40 mL) was added oxalyl chloride (58.8 mL, 117.63mmol) and 4 drops of DMF. The reaction mixture was stirred at RT for 2 hand concentrated. To the concentrate was added 2-pyrrolidinone, and thesolution was heated for 12 h. The mixture was cooled, concentrated,taken up in CH₂Cl₂, washed successively with saturated NaHCO₃, brine anddried over MgSO₄. The concentrate was purified by chromatography on anISCO instrument (eluting with 40% EtOAc/Hexanes) to give the titlecompound as a light yellow solid (6.98 g, 63%).

Step 2: 1-Phenylsulfonyldiazoacetyl)pyrrolidin-2-one

To a stirred, cooled (0° C.) solution of1-(2-tosylacetyl)pyrrolidin-2-one (6.90 g, 24.83 mmol) in MeCN (70 mL)was added Et₃N (8.21 mL, 58.91 mmol). After stirring at 0° C. for 30min., p-acetamidophenylsulfonyl azide (7.07 g, 29.45 mmol) was added andthe mixture was stirred at RT for 24 h. The mixture was concentrated,taken up in CH₂Cl₂ (3×), and a light brown solid was filtered off. Thefiltrate was concentrated and purified by ISCO (50% EtOAc/Hexanes) togive the title compound as a yellow solid (2.65 g, 36%).

Step 3: 6-Hydroxy-8-propionyl-2,3-dihydroindolizin-5-(1H)-one

A mixture of the product of step 2 (2.61 g, 8.91 mmol), methyl acrylate(5.9 g, 44.52 mmol), and Rh₂(OAc)₄ (1 mg, 0.2% mmol) in benzene (40 mL)was heated at reflux in 2 h. The mixture was cooled, concentrated, andpurified by ISCO (2% MeOH/CH₂Cl₂) to give the title compound as an offwhite solid (1.30 g, 70%).

Step 4: 5-Oxo-8-propionyl-1,2,3,5-tetrahydroindolizin-6-yltrifluoromethanesulfonate

To a stirred, cooled (0° C.) solution of6-hydroxy-8-propionyl-2,3-dihydroindolizin-5-(1H)-one (1.10 g, 4.53mmol) in CH₂Cl₂ (10 mL) was added Et₃N. After stirring for 20 min.,N-phenyltrifluoromethane sulfonamide was added in one portion. Themixture was stirred at RT for 6 h and quenched with H₂O. the mixture wasextracted with CH₂Cl₂ (3×) and the combined organic layers were driedover MgSO₄, concentrated and purified by ISCO (40% EtOAc/Hexanes) togive the title compound as a white solid (1.50 g, 99%).

Step 5:5-Oxo-6-(pyridine-2-yl)-1,2,3,5-tetrahydroindolizine-8-carboxylic acid

A mixture of 5-oxo-8-propionyl-1,2,3,5-tetrahydroindolizin-6-yltrifluoromethanesulfonate (0.50 g, 1.46 mmol), 2-trimethylstannylpyridine (0.46 g, 1.90 mmol), LiCl (0.17 g, 4.38 mmol), and (Ph₃P)₄Pd(0.12 g, 0.11 mmol) in THF (10 mL) was heated by Microwave Synthesizerat 160° C. for 20 min. The reaction was cooled, diluted with H₂O andextracted into EtOAc (3×). The organic layers were combined, dried overMgSO₄ and concentrated. The concentrate was triturated in ether to givethe salt of the title compound as a light green solid. The solid wasdissolved in MeOH (5 mL), to which was added 2 eq. of 1N NaOH and themixture was stirred for 2 h. The mixture was concentrated, taken up inH₂O, neutralized by 10% HCl, extracted with CH₂Cl₂ (3×), dried overMgSO₄, concentrated to give the title compound as a light yellow oil(0.32 g, 85%). MS (m/z, M+1): 257.1.

Step 6:N-((2S,3R)-4-((S)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)3-hydroxy-1-phenylbutan-2-yl)-5-oxo-6-(pyridin-2-yl)-1,2,3,5-tetrahydroindolizine-8-carboxamide.TFAsalt

A mixture of5-oxo-6-(pyridine-2-yl)-1,2,3,5-tetrahydroindolizine-8-carboxylic acid(0.050 g, 0.195 mmol),(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylylamino)-4-phenylbutan-2-oldihydrochloride salt (0.10 g, 0.234 mmol), HOBt (0.032 g, 0.234 mmol),EDCI (0.045 g, 0.234 mmol), and i-Pr₂NEt (0.11 g, 0.78 mmol) in DMF (2mL) was stirred at RT for 24 h. The mixture was concentrated. Theconcentrate was taken up in H₂O, and solids filtered. The filtrate waspurified by reverse phase HPLC to give the title compound. MS (m/z,M+1): 633.4.

Example 107

N-((2S,3R)-4-((8)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)3-hydroxy-1-phenylbutan-2-yl)-6-(2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamide.TFAsalt Step 1:6-(2-Fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid

A mixture of 5-oxo-8-propionyl-1,2,3,5-tetrahydroindolizin-6-yltrifluoromethanesulfonate (0.10 g, 0.292 mmol), 2-fluorophenylboronicacid (0.050 g, 0.38 mmol), and 2M Na₂CO₃ (0.75 mL, 1.46 mmol) intoluene/EtOH (4 mL, 4:1) was heated at 160° C. for 30 min. in aMicrowave Synthesizer. The mixture was cooled, and the layers wereseparated. The aqueous layer was acidified and the precipitate wasfiltered and air dried to afford the title compound (0.051 g, 64%). MS(m/z, M+1): 274.1.

Step 2:N-((2S,3R)-4-((S)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)3-hydroxy-1-phenylbutan-2-yl)-6-(2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Step 6 of Example 106. MS (m/z, M+1): 650.4.

Example 108

N-((2S,3R)-4-((8)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)3-hydroxy-1-phenylbutan-2-yl)-6-(3-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamide.TFAsalt Step 1:6-(3-Fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid

The title compound was obtained using a procedure analogous to thatdescribed in Step 1 of Example 107 (0.055 g, 70%). MS (m/z, M+1): 274.1.

Step 2:N-((2S,3R)-4-((S)-6-Ethyl-2,2-spirocyclopentylchroman-4-ylamino)3-hydroxy-1-phenylbutan-2-yl)-6-(3-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Step 6 of Example 106. MS (m/z, M+1): 650.4.

Example 109

N-((2S,3R)-4-((S)-6-fluoro-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-neopentyl-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt Step 1: 6-Fluoro-2,2-spirocyclopentyl-2,3-dihydrochromene-4-one

The title compound was obtained using a procedure analogous to thatdescribed in Step 1 of Example 105 (12.77 g, 89%).

Step 2: (R)-6-Fluoro-2,2-spirocyclopentylchroman-4-ol

To a stirred solution of (1R,2R)-TsDPEN (0.38 g, 1.05 mmol) inisopropanol (15 mL) was added di-m-chlorobis[(p-cymene)chlororuthenium(II)] (0.36 g, 0.58 mmol) and Et₃N (0.21 g, 2.10 mmol). The mixture washeated at 80° C. for 1 h, cooled, then concentrated to dryness. Theresidue was dissolved in MeCN (10 mL) and added to a solution of6-fluoro-2,2-spirocyclopentyl-2,3-dihydrochromene-4-one (12.77 g, 58.01mmol) in MeCN (100 mL). To the mixture was added a solution ofHCO₂H/Et₃N (12 mL, 5:2, Fluka). The reaction mixture was stirred at RTfor 24 h, concentrated and purified by chromatography on an ISCO (10%EtOAc/Hexanes) to give the title compound as a white solid (10.50 g,81%).

Step 3: (S)-4-Azido-6-fluoro-2,2-spirocyclopentylchroman

The title compound was obtained using a procedure analogous to thatdescribed in Step 3 of Example 105 (10.50 g, 95%).

Step 4: (S)-6-Fluoro-2,2-spirocyclopentylchroman-4-amine

The title compound was obtained using a procedure analogous to thatdescribed in Step 4 of Example 105 (6.66 g, 71%). MS (m/z, M+1): 206.1.

Step 5:(2R,3S)-3-Amino-1-((S)-6-fluoro-2,2-spirocyclopentylchroman-4-ylylamino)-4-phenylbutan-2-oldihydrochloride salt

The title compound was obtained using a procedure analogous to thatdescribed in Step 5 of Example 105 (9.50 g, 100%). MS (m/z, M+1): 385.3.

Step 6: 1-Neopentyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

A mixture of methyl coumalate (1.0 g, 6.49 mmol) and neopentylamine washeated at 80° C. for 16 h. The mixture was cooled, taken up in EtOAc,washed with H₂O, dried over MgSO₄, concentrated, and purified bychromatography on an ISCO (30% EtOAC/Hexanes) to give theN-neopentyl-methyl ester intermediate as a light brown oil. The residuewas dissolved in THF (3 mL), added LiOH (0.093 g) and 0.2 mL of H₂O,stirred at RT overnight, concentrated, taken up in H₂O, acidified,extracted with CH₂Cl₂ (3×), dried over MgSO₄, concentrated to give thetitle compound as a light brown solid (0.135 g, 10%). MS (m/z, M+1):210.2.

Step 7:N-((2S,3R)-4-((S)-6-fluoro-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-neopentyl-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Step 6 of Example 106. MS (m/z, M+1): 576.4.

Example 110

1-Cyclopentyl-N((2S,3R)-4-((S)-6-fluoro-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamideTFA salt

The title compound was obtained using a procedure analogous to thatdescribed in Step 6 of Example 105. MS (m/z, M+1): 657.4.

Example 111

1-Cyclopentyl-N((2S,3R)-4-((S)-6,8-difluoro-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Steps 1-5 of Example 105 and step 6 of Example 106. MS(m/z, M+1): 675.4.

Example 112

1-Cyclopentyl-N((2S,3R)-4-((S)-6-fluoro-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt Step 1: 1-Cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

A mixture of methyl coumalate (3.00 g, 19.46 mmol) and cyclopentylamine(4.97 g, 58.40 mmol) was stirred at RT for 24 h, and purified bychromatography on an ISCO (30% EtOAc/Hexanes) to give the methyl esteras a light yellow oil. The residue was dissolved in THF/H₂O (30 mL,29:1) to which was added LiOH (0.60 g, 13.56 mmol). The reaction mixturewas stirred at RT overnight, concentrated, taken up in H₂O, andacidified with 10% HCl. The off-white precipitated solid, the titlecompound, was filtered and air dried (1.20 g, 30%). MS (m/z, M+1):208.2.

Step 2:1-Cyclopentyl-N((2S,3R)-4-((S)-6-fluoro-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Step 6 of Example 105. MS (m/z, M+1): 574.3.

Example 113

1-Cyclopentyl-N((2S,3R)-4-((S)-6,8-difluoro-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Step 6 of Example 105. MS (m/z, M+1): 592.3.

Example 114

N-((2S,3R)-4-((S)-6,8-difluoro-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-neopentyl-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Step 6 of Example 105. MS (m/z, M+1): 594.3.

Example 115

N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-neopentyl-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Step 6 of Example 105. MS (m/z, M+1): 586.4.

Example 116

1-Cyclopentyl-N((2S,3R)-4-((8)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Example 105. MS (m/z, M+1): 653.4.

Example 117

1-Cyclopentyl-N((2S,3R)-4-((8)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Example 105. MS (m/z, M+1): 570.3.

Example 118

1-Isobutyl-N((2S,3R)-4-((8)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt Step 1: 1-Isobutyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

The title compound was obtained using a procedure analogous to thatdescribed in Step 1 of Example 112 (0.20 g, 40%). MS (m/z, M+1): 196.1.

Step 2:1-Isobutyl-N((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Step 6 of Example 105. MS (m/z, M+1): 558.3.

Example 119

1-(2,2,2-trifluoroethyl)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Example 118. MS (m/z, M+1): 584.3.

Example 120

1-(Phenyl)-N((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Example 118. MS (m/z, M+1): 578.3.

Example 121

1-Cyclopentyl-N((2S,3R)-4-((S)-6-bromo-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide.TFAsalt Step 1: 6-Bromo-2,2-spirocyclopentyl-2,3-dihydrochromene-4-one

The title compound was obtained using a procedure analogous to thatdescribed in Step 1 of Example 105. (20.50 g, 97%).

Step 2: (R)-6-Bromo-2,2-spirocyclopentylchroman-4-ol

The title compound was obtained using a procedure analogous to thatdescribed in Step 2 of Example 112. (9.0 g, 50%).

Step 3: (S)-4-Azido-6-bromo-2,2-spirocyclopentylchroman

The title compound was obtained using a procedure analogous to thatdescribed in Step 3 of Example 105. (8.0 g, 81%).

Step 4: (S)-6-Bromol-2,2-spirocyclopentylchroman-4-amine

The title compound was obtained using a procedure analogous to thatdescribed in Step 4 of Example 105. (4.00 g, 52%). MS (m/z, M+1): 267.1.

Step 5: tert-Butyl(2R,3S)-4-((S)-6-bromo-2,2-spirocyclopentylchroman-4-ylylamino)-3-hydroxyl-1-phenylbutan-2-ylcarbamate

A mixture of (S)-6-bromo-2,2-spirocyclopentylchroman-4-amine (4.0 g,14.18 mmol), t-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate(3.73 g, 14.18 mmol), and LiClO₄ (0.15 g, 1.42 mmol) in p-dioxane (60mL) was heated at 70° C. for 16 h. The mixture was cooled andconcentrated. The crude residue was purified by chromatography on anISCO (40% EtOAc/Hexanes) to give the title compound as a white solid(7.0 g, 91%). MS (m/z, M+2): 430.2.

Step 6:(2R,3S)-4-((S)-6-neopentyl-2,2-spirocyclopentylchroman-4-ylylamino)-3-hydroxyl-1-phenylbutan-2-ol.2TFAsalt

The title compound was obtained by stirring the product of Step 5 with asolution of TFA in ether or dioxanes. The solution was concentrated anddried under reduced pressure to yield the title compound TFA salt. MS(m/z, M+2): 330.2.

Step 7:1-Cyclopentyl-N((2S,3R)-4-((S)-6-bromo-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Step 6 of Example 105. MS (m/z, M+2): 718.3.

Example 122

1-Cyclopentyl-N((2S,3R)-4-((S)-6-bromo-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Example 121. MS (m/z, M+2): 635.3.

Example 123

1-Isobutyl-N((2S,3R)-4-((S)-6-bromo-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Example 121. MS (m/z, M+2): 623.3.

Example 124

1-Cyclopentyl-N((2S,3R)-4-((S)-6-neopentyl-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide.TFAsalt Step 1: (1S,5S)-9-Neopentyl-9-bora-bicyclo[3.3.1]nonane

To a stirred, cooled (78° C.) solution of 9-methoxy-BBN (20 mL, 20.0mmol, 1.0M in Hexanes) in THF (40 mL) was added 2,2-dimethylpropylmagnesium chloride (20 ml, 20.0 mmol). After stirring at −78° C. in 3 h,the mixture was quenched by pentane, warmed to RT, filtered the whitesolid. The filtrate was concentrated to give the light yellow oil (3.98g, 100%).

Step 2: Tert-Butyl(2R,3S)-4-((S)-6-neopentyl-2,2-spirocyclopentylchroman-4-ylylamino)-3-hydroxyl-1-phenylbutan-2-ylcarbamate.2TFA salt

A mixture of tert-butyl(2R,3S)-4-((S)-6-bromo-2,2-spirocyclopentylchroman-4-ylylamino)-3-hydroxyl-1-phenylbutan-2-ylcarbamate(0.50 g, 0.92 mol), (1S,5S)-9-neopentyl-9-bora-bicyclo[3.3.1]nonane(0.25 g, 1.28 mmol), (Ph₃P)₄Pd, and 5 N NaOH (0.45 mL, 2.30 mmol) in THF(10 mL) was heated at 80° C. in 24 h. The mixture was concentrated todryness, dissolved in p-dioxane (10 mL) and added 4 M HCl (1.5 mL, 4.60mmol) and stirred in 24 h. The mixture was concentrated and purified byreverse phase HPLC to give the white solid (0.276 g, 45%). MS (m/z,M+1): 437.3.

Step 3:1-Cyclopentyl-N42S,3R)-4-((S)-6-neopentyl-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Step 6 of Example 105. MS (m/z, M+1): 709.4.

Example 125

1-Cyclopentyl-N((2S,3R)-4-((S)-6-neopentyl-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Example 105. MS (m/z, M+1): 626.4.

Example 126

N-((2S,3R)-4-((S)-6-Ethyl-2,2-spirocyclobutylchroman-4-ylamino)3-hydroxy-1-phenylbutan-2-yl)-6-(2-fluorophenyl)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Example 106. MS (m/z, M+1): 636.3.

Example 127

1-Cyclopentyl-N((2S,3R)-4-((8)-6-fluoro-2,2-spirocyclobutylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained using a procedure analogous to thatdescribed in Example 105. MS (m/z, M+1): 643.3.

Example 128

1-cyclopentyl-N-((2S,3R)-4-((8)-6-ethyl-2,2-spirocyclohexyl-chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamideStep 1: 6-ethyl-2,2-spirocyclohexylchroman-4-one

A solution of cyclohexyl ketone (8 ml, 78 mmol),1-(5-ethyl-2-hydroxyphenyl)ethanone (8 g, 48.7 mmol), and pyrrolidine(1.6 ml, 19.5 mmol) were refluxed using a Dean Stark trap for 12 h. Thecooled reaction mixture was diluted with 100 ml ether, washed with 30 mlHCl (aq., 5M), dried over MgSO₄ and evaporated. Column chromatography(3% EtOAc in Hexanes) gave 6-ethyl-2,2-spirocyclohexylchroman-4-one as ayellow oil 9.4 g (38.5 mmol, 79%). MS m/z: 245 (M+1).

Step 2: (R)-6-ethyl-2,2-spirocyclohexylchroman-4-ol

A solution of (S)-2 Methyl-CBS-oxazaborolidin (1 M, 820 ul, 0.82 mmol)and borane DMS complex (2 ml, 21.3 mmol) in 25 ml toluene was cooled to−20° C. and a solution of 6-ethyl-2,2-spirocyclohexylchroman-4-one (17a,4 g, 16.4 mmol) in 9 ml THF was added slowly over a period of 2.5 h. Thereaction mixture was stirred for 1.5 h at the same temperature and wasthan carefully hydrolyzed with MeOH. The mixture was washed with HCl (1M, aq.) and NaHCO₃ (sat., aq.) and the organic phase was dried overMgSO₄ and evaporated.

The crude material was used without further purification in the nextstep.

Step 3: (S)-4-azido-6-ethyl-2,2-spirocyclohexylchroman

The crude material from step 2 was dissolved in 30 ml toluene and dppa(4.8 ml, 21.5 mmol) and DBU (3.1 ml, 21.5 mmol) were added, and themixture was stirred for 12 h. Two phases were observed and the lessheavy layer was diluted with ether and washed with HCl (1 M, aq.), thenNaHCO₃ (sat., aq.), dried over MgSO₄ and evaporated under reducedpressure. Column chromatography (3% EtOAc in hexanes) gave 3.3 g (12.2mmol, 73% (over 2 steps)) of the title compound as a yellow oil MS m/z:244 (60%, M-N₂); 229(20%, M-N₃).

Step 4: (S)-6-ethyl-2,2-spirocyclohexylchroman-4-amine

(S)-4-azido-6-ethyl-2,2-spirocyclohexylchroman (3.3 g, 12.2 mmol) wasdissolved in 50 ml THF and cooled to 3° C. LAH (1 M in THF, 12.2 ml,12.2 mmol) was added and stirring was continued for 2.5 h. The reactionmixture was allowed to warm up to room temperature during this period oftime and 50 ml THF and 50 ml CH₂Cl₂ were added. 15 g NaSO₄.10H₂O wasadded carefully, the mixture was stirred 15 min and was filtered. Thefiltrate was dried over Mg504 and evaporated and the crude titlecompound (MS m/z: 229(100%, M-NH₂)), which was used without purificationin the next step.

Step 5: Tert-butyl(2S,3R)-4-((S)-6-ethyl-2,2-spirocyclohexyl-chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate

(S)-6-Ethyl-2,2-spirocyclohexylchroman-4-amine (433 mg, 1.95 mmol) wasmixed with 1 ml IPA and tert-butyl(S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (393 mg, 1.5 mmol) andthe mixture was heated in a microwave to 125° C. for 15 min. The mixturewas diluted with 2 ml DMF and purified on the prep HPLC (Gilson) to give510 mg of the title compound as its TFA salt (0.82 mmol, 54%, whitesolid, MS m/z: 509(100%, M+1)).

Step 6:(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-spirocyclohexylchroman-4-ylamino)-4-phenylbutan-2-ol

Tert-butyl(2S,3R)-4-((S)-6-ethyl-2,2-spirocyclohexyl-chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate.TFA(510 mg, 0.82 mmol) was dissolved in 3 ml THF and HCL (4M in dioxane, 5ml, 20 mmol) was added. The reaction was stirred for 3 h and evaporated.The crude product (white solid, di-HCl salt, MS m/z: 409(100%, M+1)) wasused without purification in the next step.

Step 7:1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclohexyl-chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide

(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-spirocyclohexylchroman-4-ylamino)-4-phenylbutan-2-ol(48 mg, 0.1 mmol) was dissolved in 1 ml DMF and1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxylicacid (29 mg, 0.1 mmol), hatu (38 mg, 0.1 mmol) and diisopropyl-ethylamine (50 ul, 0.3 mmol) were added. The mixture was stirred for 2 h and5 drops from a Pasteur pipette of HCl (5M, aq.) was added. The mixturewas purified, without work up, on a prep HPLC (Gilson) to give the titlecompound as a white TFA salt. MS m/z: 681 (M+1).

The following Examples 129-142 were obtained using a procedure analogousto that described in Example 128.

Example 129

1-cyclohexyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclohexyl-chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide(MS m/z: 612 (100%, M+1)) Example 130

1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocycloheptyl-chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide(MS m/z: 695(100%, M+1)). Example 131

1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclopentyl-6-methylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide(MS m/z: 653 (100%, M+1)). Example 132

1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclopentyl-6-methylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide(MS m/z: 570 (100%, M+1)) Example 133

N-((2S,3R)-4-((S)-2,2-spirocyclopentyl-6-methylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-neopentyl-6-oxo-1,6-dihydropyridine-3-carboxamide(MS m/z: 572 (100%, M+1)) Example 134

1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclopentyl-6-(trifluoromethoxy)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide(MS m/z: 723 (100%, M+1)). Example 135

1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclopentyl-6-(tri-fluoromethoxy)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (MS m/z: 640 (100%, M+1)). Example 136

N-((2S,3R)-4-((S)-2,2-spirocyclopentyl-6-(trifluoro-methoxy)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-neopentyl-6-oxo-1,6-dihydropyridine-3-carboxamide(MS m/z: 642 (100%, M+1)). Example 137

1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclopentyl-6-iso-propylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide(MS m/z: 681 (100%, M+1)). Example 138

1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclopentyl-6-iso-propylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide (MS m/z: 598 (100%, M+1)). Example 139

N-((2S,3R)-4-((S)-2,2-spirocyclopentyl-6-isopropylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-(3-methylcyclohexyl)-6-oxo-1,6-dihydropyridine-3-carboxamide(MS m/z: 626 (100%, M+1)). Example 140

1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-(-methyl)-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide

The title compound (designated diastereomer was purified by HPLC in Step5) was obtained as a white TFA salt using a procedure analogous to thatdescribed in Example 139 (referring back to Example 128). MS m/z: 681(100%, M+1)). The remaining 3 diastereomers were isolated from the HPLCfractions as a mixture in Step 5, and concentrated to provide a whiteTFA salt. MS m/z: 681 (100%, M+1).

Example 141

1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-(-methyl)-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained as a white TFA salt using a procedureanalogous to that described in Example 139 (referring back to Example128). MS m/z: 598 (100%, M+1). The remaining 3 diastereomers wereisolated from the HPLC fractions as a mixture in Step 5, andconcentrated to provide a white TFA salt. MS m/z: 598 (100%, M+1)).

Example 142

4-chloro-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamide

The title compound was obtained as a white TFA salt using a procedureanalogous to that described in Example 139 (referring back to Example128). MS m/z: 627(100%, M+1).

Example 143

N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamideStep 1: 6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid

4-chloro-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid (100 mg,0.4 mmol) was dissolved in 3 ml EtOH and Pd/C (25 mg) was added. A H₂balloon was attached to the reaction vessel and the mixture was stirredfor 4 h. The reaction was filtered through a pad of Celite®,concentrated and used without further purification in the next reaction.MS m/z: 217(100%, M+1)).

Step 2:N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamide

The title compound was obtained as a white TFA salt using a procedureanalogous to that described in Example 128. MS m/z: 593 (100%, M+1).

Example 144

4-chloro-N-((2S,3R)-3-hydroxy-4-((S)-6-isopropyl-2,2-spirocyclopentylchroman-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamide MS m/z: 641 (100%, M+1) Example 145

N-((2S,3R)-4-((S)-2,2-spirocyclopentylchroman-6-isopropylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamideMS m/z: 607(100%, M+1) Example 146

N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamideMS m/z: 579(100%, M+1) Example 147

4-chloro-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxamideMS m/z: 613 (100%, M+1)) Example 148

1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide

(2R,3S)-3-amino-1-((S)-2,2-dimethylchroman-4-ylamino)-4-phenylbutan-2-olwas dissolved in 250 ul DMF and1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxylicacid (8 mg, 0.027 mmol) HATU (10 mg, 0.027 mmol) anddiisopropylethylamine (DIEA, 13 ul, 0.081 mmol) were added. The mixturewas stirred for 2 h and 2 drops HCl (5 M, aq.) was added. The mixturewas loaded directly, without further work up, onto a prep HPLC (Gilson)system and purified to afford the title compound as a white TFA salt. MSm/z: 639(100%, M+1).

The following Examples 149-150 were synthesized by a method analogous tothat described in Example 148.

Example 149

1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamideMS m/z: 556 (100%, M+1) Example 150

1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamideMS m/z: 633 (30%, M+1)) Example 151

1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo-butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridazine-3-carboxamideStep 1:Cyclopentyl-1-cyclopentyl-6-oxo-1,6-dihydropyridazine-3-carboxylate

6-Oxo-1,6-dihydropyridazine-3-carboxylic acid (1 g, 7.14 mmol) wasstirred with cyclopentyl iodide (2.05 ml, 17.8 mmol) and potassiumcarbonate (3 g, 21.4 mmol) in 15 ml DMF for 14 h at room temperature. 50ml CH₂Cl₂ was added and the reaction mixture was filtered. The filtratewas concentrated and the title compound was purified by prep HPLC.Yield: 20 mg (0.072 mmol, 1%, MS m/z: 277(100%, M+1)).

Step 2: 1-cyclopentyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid

Cyclopentyl-1-cyclopentyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (20mg, 0.072 mmol) was dissolved in 2 ml THF/water (1/1) and 2 ml NaOH (5M,aq.) was added. The reaction was stirred at 40° C. for 2 h and 5 ml HCl(5M, aq.) was added. The reaction was concentrated and 10 ml ofCH₂Cl₂/MeOH (1/1) was added and the reaction was sonicated for 10 minand filtered. The filtrate was concentrated and used in the next stepwithout further purification. Yield: 11 mg (0.052 mmol, 73%, film, MSm/z: 209(100%, M+1).

Step 3:1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo-butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridazine-3-carboxamide

The title compound was obtained as a white TFA salt using a procedureanalogous to that described in Example 148. MS m/z: 571 (100%, M+1).

Example 152

1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide

The title compound was obtained as a white TFA salt using a procedureanalogous to that described in Example 128. MS m/z: 625(100%, M+1)).

Example 153

1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained as a white TFA salt using a procedureanalogous to that described in Example 150. MS m/z: 542 (100%, M+1)).

Example 154

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-4-methyl-2,2-spiro-cyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamideStep 1: 6-ethyl-4-methyl-2,2-spirocyclobutylchroman-4-ol

6-ethyl-2,2-spirocyclobutylchroman-4-one (0.32 g, 1.500 mmol) wasdissolved in 10 ml THF and cooled to 0° C. While stirring, methyllithium (1.6 m solution in diethyl ether (4.7 ml, 7.5 mmol)) was addeddrop wise to the reaction and the cooling bath was removed after theaddition. The reaction mixture was stirred for 2 h at RT. 30 ml of Sat.NH4Cl (aq) was added and the mixture was diluted with 100 ml EtOAc. Thephases were separated and the aqueous layer was extracted (2×) withEtOAc 50 ml (each). The combined organic layers were dried over Mg504,filtered and concentrated. Column chromatography gave the title compound(0.267 g, 0.80 mmol, 54% yield) as a yellow oil. MS m/z: 215(100%,M-OH).

Step 2: 4-azido-6-ethyl-4-methyl-2,2-spirocyclobutylchroman

A solution of 6-ethyl-4-methyl-2,2-spirocyclobutylchroman-4-ol (0.276 g,0.832 mmol) and azidosodium (0.541 g, 8.32 mmol) was dissolved/suspendedin 5 ml chloroform and cooled to 0° C. A solution of2,2,2-trifluoroacetic acid (0.320 ml, 4.16 mmol) in 2 ml chloroform wasadded over a period of 2 h via syringe pump. After the addition thereaction was warmed up to room temperature and stirring was continuedfor 2 h. The reaction mixture was diluted with 10 ml of water andextracted 2× with 50 ml dichloromethane. Glass column chromatographygave the title compound (0.2100 g, 0.326 mmol, 39.3% yield, MS m/z:215(100%, M-N₃)).

Step 3: 6-ethyl-4-methyl-2,2-spirocyclobutylchroman-4-amine

4-azido-6-ethyl-4-methyl-2,2-spirocyclobutylchroman (0.210 g, 0.3260mmol) was dissolved in 2 ml THF and cooled to 0° C. Then, lithiumaluminum hydride (1.0M solution in tetrahydrofuran, 3.26 ml, 3.26 mmol)was added drop wise and stirring was continued at 0° C. for 1 h and atRT for 2 h. The reaction mixture was diluted with 10 ml THF and 40 mldichloromethane and 4 g NaSO₄.10H₂O was added carefully. The mixture wasfiltered, dried over Mg504 evaporated and the title compound (0.177 g,0.306 mmol, 93.9% yield, MS m/z: 215(100%, M-NH₂)) used in the nextreaction without further purification.

Step 4: Tert-butyl(2S,3R)-4-(6-ethyl-4-methyl-2,2-spirocyclo-butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate

6-ethyl-4-methyl-2,2-spirocyclobutylchroman-4-amine (0.17700 g, 0.3064mmol) and tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate(0.323 g, 1.23 mmol) were mixed in 1 ml IPA and heated in a microwave to135° C. for 25 min. The crude product was purified without furtherworkup using a prep HPLC (Gilson), to afford the title compound (0.190g, 0.259 mmol, 84.6%) as a white TFA salt.

Step 5:(2R,3S)-3-amino-1-(6-ethyl-4-methyl-2,2-spirocyclobutyl-chroman-4-ylamino)-4-phenylbutan-2-ol

Tert-butyl(2S,3R)-4-(6-ethyl-4-methyl-2,2-spirocyclo-butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate(0.190 g, 0.259 mmol) was dissolved in 1 ml dioxane and HCl (4 M indioxane, 0.648 ml, 2.59 mmol) was added at room temperature. Thereaction mixture was stirred for 4 h at RT and evaporated. The crudeproduct was purified on the prep HPLC to give the title compound (0.160g, 0.257 mmol, 99.2% yield) as a white HCl salt. MS m/z: 395(100%, M+1).

Step 6:1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-4-methyl-2,2-spiro-cyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide

(2R,3S)-3-amino-1-(6-ethyl-4-methyl-2,2-spirocyclobutyl-chroman-4-ylamino)-4-phenylbutan-2-ol(0.0311 g, 0.05 mmol) and1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxylicacid (0.0145 g, 0.05 mmol) were dissolved in 0.5 ml DMF andN-ethyl-N-isopropylpropan-2-amine (0.0348 ml, 0.2 mmol) and HATU (0.0190g, 0.05 mmol) were added at room temperature. The reaction mixture wasstirred at RT for 2 h. 2 drops of HCl (5 M, aq., from a Pasteur pipette)were added. The title compound was purified from the mixture, withoutfurther workup, by prep HPLC (Gilson) to give the title compound as awhite TFA salt. MS m/z: 667(80%, M+1).

Example 155

1-cyclopentyl-N-((2S,3R)-4-(6-ethyl-4-methyl-2,2-spiro-cyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained as a white TFA salt using a procedureanalogous to that described in Example 154. MS m/z: 584 (100%, M+1)).

Example 156

N-((2S,3R)-4-((S)-6-bromo-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamideStep 1:(2R,3S)-3-amino-1-((S)-6-bromo-2,2-spirocyclobutylchroman-4-ylamino)-4-phenylbutan-2-ol

Tert-butyl(2S,3R)-4-((S)-6-bromo-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate(0.132 g, 0.248 mmol) was dissolved in 2 ml of dioxane, and HCl (4 M indioxane, 3.10 ml, 12.4 mmol) were added at RT. The reaction was stirredfor 2 h, then concentrated. The crude title compound (HCl salt) (0.128g, 0.254 mmol, 102% yield) was used in the next step without furtherpurification. MS m/z: 431 (100%, M+1); 433 (100%, M+3).

Step 2:N-((2S,3R)-4-((S)-6-bromo-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclonentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide

(2R,3S)-3-amino-1-((S)-6-bromo-2,2-spirocyclobutylchroman-4-ylamino)-4-phenylbutan-2-ol(0.030 g, 0.06 mmol) and1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxylicacid (0.017 g, 0.06 mmol) were dissolved in 0.5 ml DMF andN-ethyl-N-isopropylpropan-2-amine (0.041 ml, 0.24 mmol) and HATU (0.023g, 0.060 mmol) were added at room temperature. The reaction mixture wasstirred at room temperature for 2 h. 2 drops of HCl (5 M, aq.) wereadded. The mixture was purified, without further workup, on a prep HPLC(Gilson) to give the title compound as a white TFA salt. MS m/z: 703(100%, M+1); 705(100%, M+3).

Example 157

N-((2S,3R)-4-((8)-6-bromo-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-1,6-dihydropyridine-3-carboxamide

The title compound was obtained as a white TFA salt using a procedureanalogous to that described in Example 156. MS m/z: 620 (100%, M+1); 622(100%, M+3).

Example 158

2-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide

In a 3 mL vial, 2-cyclopentyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid (32.6 mg, 127 mmol) was dissolved in DMF (1 mL). To this was addedHATU (48.5 mg, 0.127 mmol), followed by(2R,3S)-3-amino-1-((S)-6-ethyl-2,2-dimethylchroman-4-ylamino)-4-phenylbutan-2-oldihydrochloride (50 mg, 0.116 mmol) and DIPEA (0.05 ml). Reaction wasstirred for 6 h at RT. Reaction was shown to be complete by LCMS andpurified by reverse phase LC to give the title compound. MS m/z: 634.3[M+H]

Example 159

N-((2S,3R)-4((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxo-6-(2-fluorophenyl)-1,2,3,5-tetrahydroindolizine-8-carboxamide.TFA salt Step 1: 5-methyl-1-(2-tosylacetyl)pyrrolidin-2-one

The title compound was obtained as a golden-colored oil using aprocedure analogous to that described in Step 1 of Example 106. MS m/z:296.4 (M+1).

Step 2: 5-Methyl-1-(2-tosyl-2-diazoacetyl)pyrrolidin-2-one

The title compound was obtained as a yellow solid using a procedureanalogous to that described in Step 2 of Example 106. MS m/z: 294.3(M-N₂).

Step 3: Methyl6-hydroxy-3-methyl-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate

The title compound was obtained as a grey solid using a procedureanalogous to that described in Step 3 of Example 106. MS m/z: 224.1(M+1).

Step 4: Methyl3-methyl-5-oxo-6-(trifluoromethylsulfonyloxy)-1,2,3,5-tetrahydroindolizine-8-carboxylate

The title compound was obtained as a golden-colored oil using aprocedure analogous to that described in Step 4 of Example 106. MS m/z:356.1 (M+1).

Step 5:6-(2-Fluorophenyl)-3-methyl-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylicacid

To a microwave tube was addedmethyl-3-methyl-5-oxo-6-(trifluoromethylsulfonyloxy)-1,2,3,5-tetrahydroindolizine-8-carboxylate(94 mg, 0.26 mmol), 2-fluorophenylboronic acid (37 mg, 0.26 mmol,Aldrich), and 2 M sodium carbonate (0.65 mL, 1.30 mmol). To this wasadded 4 mL of toluene, 0.25 mL of EtOH, and Pd(PPh₃)₄ (20 mg, 0.17 mmol,Aldrich). The tube was sealed and treated in Emry's optimizer for 15 minat 160° C. The aqueous phase was separated and acidified to pH 2 with 2N HCl and extracted with EtOAc (3×). The combined EtOAc layers werewashed with brine, dried over MgSO₄, and concentrated in vacuo to give40 mg (53%) of the title compound as a light brown residue. MS m/z:288.1 (M+1).

Step 6:N-((2S,3R)-4((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxo-6-(2-fluorophenyl)-1,2,3,5-tetrahydroindolizine-8-carboxamide.TFAsalt

To a solution of(2S,3R)-3-amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-oldihydrochloride salt and6-(2-fluorophenyl)-3-methyl-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylicacid (about 1 eq.) in 1 mL of DMF, was added DIEA (about 3-5 eq.) andHATU (about 1.1 eq.). The solution was stirred at room temperature andmonitored by LC-MS for product formation. The reaction mixture waspurified by reverse phase HPLC to give the title compound as a colorlessresidue. MS m/z: 664.3 (M+1).

Example 160

1-cyclohexyl-N-((2S,3R)-4((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt Step 1: Methyl 1-cyclohexyl-6-oxo-1,6-dihydropyridine-3-carboxylate

To a solution of 6-oxo-6H-pyran-3-carboxylate (1.14 g, 7.4 mmol,Aldrich) and 20 mL of MeOH was added cyclohexylamine (2.50 mL, 21.9mmol, Aldrich). The solution was stirred at reflux for 16 hours, thenconcentrated in vacuo. The crude material was chromatographed through aRedi-Sep® pre-packed silica gel column (12 g), eluting with 5% to 20%EtOAc:hexane to give 460 mg (26%) of the title compound as a dark yellowoil. MS m/z: 236.4 (M+1).

Step 2: 1-Cyclohexyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

To a solution of methyl1-cyclohexyl-6-oxo-1,6-dihydropyridine-3-carboxylate (100 mg, 0.43 mmol)in 10 mL of THF:MeOH (3:1) was added 1M LiOH (1 mL, 1 mmol). Thesolution was stirred at room temperature until starting material wasconsumed as determined by LC-MS. The solution was then concentrated invacuo, acidified with 2 N HCl to pH 2, and extracted with EtOAc (3×).The combined EtOAc layers were washed with brine, dried over MgSO₄, andconcentrated in vacuo to give 60 mg (63%) of the title compound as agolden yellow solid. MS m/z: 222.1 (M+1).

Step 3: 1-cyclohexyl-N-((2S,3R)-4((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained as a colorless residue using a procedureanalogous to that described in step 6 of Example 161, by reacting(2S,3R)-3-amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-oldihydrochloride salt and1-cyclohexyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid. MS m/z: 598.4(M+1).

Example 161

1-(3-Methylcyclohexyl)-N-((2S,3R)-4((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt Step 1:1-(3-Methylcyclohexyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid

A solution of methyl 6-oxo-6H-pyran-3-carboxylate (620 mg, 4.0 mmol,Aldrich) and 3-methylcyclohexanamine (900 mg, 8.0 mmol, Pfaltz andBauer) was heated in the Emry's optimizer microwave at 150° C. for 15min. The resulting solution was transferred to a 50 mL round bottomflask with THF, then diluted with THF:MeOH to give approximately 40 mLof a 3:1 THF:MeOH solution. Add 1 M LiOH (6 mL, 6 mmol) and stir at RTovernight. The solution was concentrated in vacuo and the residue takenup in H₂O. The aqueous solution was extracted with ether (30 mL). 2 NHCl was added to acidify the aqueous solution to pH 2. The aqueoussolution was extracted with EtOAc (3×) and the combined EtOAc layersdried over MgSO₄, and concentrated in vacuo to give 200 mg (21%) of thedesired product as a light brown residue. MS m/z: 612.5 (M+1).

Step 2:1-(3-Methylcyclohexyl)-N-((2S,3R)-4((S)-6-ethyl-2,2-spirocyclopentylchroman4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide.TFAsalt

The title compound was obtained as a colorless residue using a procedureanalogous to that described in Step 6 of Example 161, by reacting(2S,3R)-3-amino-1-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-4-phenylbutan-2-oldihydrochloride salt and1-(3-methylcyclohexyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid. MSm/z: 612.5 (M+1).

Example 162

2-cyclopentyl-N-((2S,3R)-4((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide.TFAsalt Step 1: 2-Cyclopentyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylicacid

To a solution of methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate (780mg, 3.8 mmol, Bionet), potassium carbonate (650 mg, 4.7 mmol, Aldrich),and 6 mL of DMF was added cyclopentyl iodide (0.52 mL, 4.5 mmol,Aldrich). The solution was stirred at RT for 4 h, then diluted with 50mL of water. The solids were filtered and washed with CH₂Cl₂ and EtOAc.The filtrate was concentrated in vacuo and chromatographed through aRedi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 15%EtOAc:hexane to give 240 mg (23%) of methyl2-cyclopentyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylate as anoff-white solid. MS m/z: 272.3 (M+1).

The solids were dissolved in 10 ml of THF:MeOH (3:1) and 1M LiOH (2 mL,2.0 mmol) was added. After stirring at room temperature overnight, thepH was adjusted to 2 with 2N HCl and extracted with EtOAc (3×). Thecombined organic layers were washed with brine, dried over MgSO₄, andconcentrated in vacuo to give 230 mg (100%) of the title compound as awhite solid. MS m/z: 258.0 (M+1).

Step 2:2-cyclopentyl-N-(((2S,3R)-4((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-O-1-oxo-1,2-dihydroisoquinoline-4-carboxamide.TFAsalt

The title compound was obtained as an off-white solid using a procedureanalogous to that described in Step 6 of Example 161, by reacting(2S,3R)-3-amino-1-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-4-phenylbutan-2-oldihydrochloride salt and2-cyclopentyl-1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid. MS m/z:620.7 (M+1).

Example 163

1-cyclopentyl-N-((2S,3R)-4((S)-6-ethyl-2,2-dimethylchroman-4-ylamino))-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamideTFA salt

The title compound was obtained as a light brown residue using aprocedure analogous to that described in Step 6 of Example 159, byreacting(2S,3R)-3-amino-1-((S)-6-ethyl-2,2-dimethylchroman-4-ylamino)-4-phenylbutan-2-oldihydrochloride salt and1-cyclopentyl-6-oxo-1,2-dihydropyridine-3-carboxylic acid. MS m/z: 558.3(M+1).

Example 164

1-Cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamideStep 1: methyl 6-(cyclopentyloxy)-5-(pyridin-2-yl)nicotinate

A solution of methyl 5-bromo-6-(cyclopentyloxy)nicotinate (4.53 g, 15.1mmol) and 2-(tributylstannyl)pyridine (5.00 g, 13.6 mmol) was stirred in100 mL of DMF at 120° C. for 6 h. The resulting solution was cooled andconcentrated in vacuo. The crude reaction mixture was then partitionedbetween EtOAc and water. The layers were separated and the aqueous layerwas extracted 1×EtOAc. The organic phases were combined, washed 3×brine, dried over MgSO₄, filtered and concentrated under reducedpressure. The residue was taken up in CH₂Cl₂ and loaded on to a 40 gpre-packed silica gel column. Elution with 0-30% EtOAc:hexanes providedthe title compound as an off-white powder (1.71 g, 38%). MS m/z: 299(M+1).

Step 2: methyl 6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxylate

A solution of boron tribromide (1.0 M in CH₂Cl₂, 10.6 mL, 10.6 mmol) wasadded to a solution of the nicotinate (Step 1, 1.44 g, 4.81 mmol) in 40mL of CH₂Cl₂ at −10° C. The cooling bath was removed and stirring wascontinued at room temperature for 16 h. The reaction mixture wasneutralized with saturated NaHCO₃ solution and the resultant tanprecipitate was filtered and washed with copious amounts of H₂O to give0.77 g (70%) of the title compound. MS m/z: 231 (M+1).

Step 3: methyl1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxylate

Methyl 6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxylate (Step 2,210 mg, 0.91 mmol), cyclopentyl iodide (196 mg, 1.0 mmol) and potassiumcarbonate (150 mg, 1.1 mmol) were stirred at room temperature in 2 mL ofDMF for 24 h. The reaction mixture was quenched with H₂O and extracted3× with EtOAc. The combined organic extracts were washed 3× with brine,dried over MgSO₄, filtered and concentrated in vacuo. The residue wastaken up in CH₂Cl₂ and loaded on to a 5 g pre-packed silica gel columnand purified. Elution with 0-30% EtOAc:hexanes gave the title compoundas an off-white powder (57 mg, 21%). MS m/z: 299 (M+1).

Step 4:1-Cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxylicacid

The pyridone (Step 3, 57 mg, 0.19 mmol) and lithium hydroxide (16 mg,0.38 mmol) were stirred at room temperature in a solution of 2 mL ofMeOH and 0.3 mL of H₂O, for 2 h. The reaction mixture was diluted withwater and the pH was adjusted to pH ˜2 with concentrated H₂SO₄. Themixture was extracted 3×20% IPA:CHCl₃ and the combined organic fractionswere dried over MgSO₄ and concentrated. The crude residue was purifiedto obtain the title compound as a white powder (48 mg, 89%). MS m/z: 285(M+1).

Step 5:1-Cyclopentyl-N-((2S,3R)-4-((R)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide

The acid (Step 4, 19 mg, 0.066 mmol) was dissolved in 2 mL of DMF and(2R,3S)-3-amino-1-((R)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-4-phenylbutan-2-ol(25 mg, 0.066 mmol), HOBt (10 mg, 0.066 mmol), N,N-diisopropylethylamine(17 mg, 0.13 mmol) and EDCI (13 mg, 0.066 mmol) were added sequentially.The reaction mixture was stirred at room temperature for 10 h before itwas quenched with 2 drops of 5 N HCl. The residue was purified directlyby reverse phase HPLC (elution 5-95% CH₃CN(0.1% TFA):water (0.1% TFA)).The appropriate fractions were combined and concentrated to give thecorresponding TFA salt of the title compound as an off-white powder (10mg, 23%). MS m/z: 647 (M+1).

Example 165

N-((2S,3R)-4((R)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-isopropyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide

The title compound was obtained, as an off-white solid, by a methodanalogous to that described in Example 164. MS m/z: 635 (M+1).

Example 166

N-((2S,3R)-4-((R)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-isopropyl-6-oxo-5-(pyridin-4-yl)-1,6-dihydropyridine-3-carboxamideStep 1: Methyl 6-(cyclopentyloxy)-5-(pyridin-4-yl)nicotinate

Methyl 5-bromo-6-(cyclopentyloxy)-1,6-dihydropyridine-3-carboxylate(2.50 g, 7.94 mmol) was dissolved in DME (10 mL) and pyridin-4-ylboronicacid (813 mg, 6.61 mmol), DPPF-PdCl₂ (108 mg, 0.13 mmol, Strem) andwater (0.5 mL, 28 mmol) were added. The mixture was stirred at 40° C.for 4 h. The reaction mixture was cooled to RT, diluted with H₁₀ andextracted 3× with EtOAc. The combined organic extracts were washed 1×with brine, dried (MgSO₄), filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (40 g pre-packedcolumn, elution 0-30% EtOAc:hexanes) to give the title compound (608 mg,31%). MS m/z: 299 (M+1).

Step 2: Methyl 6-oxo-5-(pyridin-4-yl)-1,6-dihydropyridine-3-carboxylate

The title compound was obtained, as a brown solid, by a method analogousto that described in Step 2 of Example 164. MS m/z: 231 (M+1).

Step 3: Methyl1-isopropyl-6-oxo-5-(pyridin-4-O-1,6-dihydropyridine-3-carboxylate

Methyl1-isopropyl-6-oxo-5-(pyridin-4-yl)-1,6-dihydropyridine-3-carboxylate wasprepared by a method analogous to that described in Step 3 of Example164. The title compound was obtained as a white solid (77 mg, 33%). MSm/z: 273 (M+1).

Step 4:1-isopropyl-6-oxo-5-(pyridin-4-O-1,6-dihydropyridine-3-carboxylic acid

1-Isopropyl-6-oxo-5-(pyridin-4-yl)-1,6-dihydropyridine-3-carboxylic acidwas synthesized by a method analogous to that described in Step 4 ofExample 164, and isolated as an off-white solid (60 mg, 82%). MS m/z:259 (M+1).

Step 5:N-((2S,3R)-4-((R)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-O-1-isopropyl-6-oxo-5-(pyridin-4-yl)-1,6-dihydropyridine-3-carboxamide

The title compound was obtained, as a brown solid, by a method analogousto that described in Step 5 of Example 164. The title compound, as a TFAsalt, was obtained as an off-white solid. MS m/z: 718 (M+1).

Example 167

N-((2S,3R)-4-((R)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-methyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamideStep 1: Methyl1-methyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxylate

Methyl 5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (57 mg,0.23 mmol), 2-(tributylstannyl)pyridine (85 mg, 0.23 mmol) andtetrakis(triphenylphosphine)palladium (13 mg, 0.012 mmol, Strem) werestirred in 1.5 mL of dioxane at 90° C. for 16 h. The reaction mixturewas cooled to RT, diluted with H₂O and extracted with EtOAc (2×). Thecombined organic extracts were washed 1× with brine, dried over MgSO₄,filtered and concentrated in vacuo. Purification of the crude residue bycolumn chromatography (4 g pre-packed column, elution 0-30%EtOAc/Hexanes) gave the title compound (22 mg, 39%) as a light yellowsolid. MS m/z: 245 (M+1).

Step 2:N-((2S,3R)-4-((R)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-methyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide

Methyl 1-methyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxylate(22 mg, 0.090 mmol) and lithium hydroxide monohydrate (4 mg, 0.090 mmol)were stirred in MeOH (5 mL) and H₂O (0.2 mL) for 24 h. The solvent wasremoved under reduced pressure and the crude acid was used directly inthe next step.

The title compound was obtained, as a brown solid, by a method analogousto that described in step 5 of Example 164, using the above acid (20 mg,0.090 mmol),(2R,3S)-3-amino-1-((R)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-4-phenylbutan-2-ol(33 mg, 0.090 mmol), HOBt (12 mg, 0.090 mmol), N,N-diisopropylethylamine(22 mg, 0.17 mmol) and EDCI (17 mg, 0.090 mmol). The corresponding TFAsalt of the title compound was obtained as an off-white solid. MS m/z:593 (M+1).

Example 168

1-ethyl-N-((2S,3R)-4-((R)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide

The title compound was obtained by a method analogous to that describedin Example 167. The title compound was obtained as an off-white solidTFA salt. MS m/z: 607 (M+1).

Example 169

1-cyclopentyl-N-((1R,2R)-4-((8)-6-ethyl-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-ylamino)-1-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamideStep 1: (R)-2-(benzyloxycarbonylamino)pent-4-enoic acid.(R)-2-(benzyloxycarbonyl)pent-4-enoic acid

The title compound was prepared from commercially availableD-allylglycine according the method described in Organic ProcessResearch & Development, 6:762-766 (2002).

Step 2: Benzyl (1R,2R)-1-hydroxy-1-phenylpent-4-en-2-ylcarbamate

To a mixture of HATU (0.915 g, 2.41 mmol),(R)-2-(benzyloxycarbonyl)pent-4-enoic acid (0.400 g, 1.60 mmol),N-methoxymethanamine hydrochloride (0.188 g, 1.93 mmol) in CH₂Cl₂ (20mL) at 0° C. was added triethylamine (0.558 ml, 4.01 mmol). The mixturewas allowed to stir at 0° C. for 20 min then warmed to RT for 30 min.The reaction was diluted with CH₂Cl₂ (20 mL) and washed with 1 M HCl (30mL), 9% Na₂CO₃ (30 mL), brine (30 mL), dried over Na₂SO₄, filteredthrough a small plug of silica gel and washed with ether (10 mL) andconcentrated. The crude material was used without further purification.MS m/z=293 [M+1]⁺. Calc'd for C₁₅H₂0N₂O₄: 292.

To a solution of (R)-benzyl1-(methoxy(methyl)amino)-1-oxopent-4-en-2-ylcarbamate (0.468 g, 1.60mmol) in THF (10 mL) at 0° C. was added phenylmagnesium bromide (1.0 Min THF, 4.80 ml, 4.80 mmol). The mixture was allowed to warm to roomtemperature and stir overnight. To the mixture was added saturatedaqueous NH₄Cl (10 mL). The volatiles were removed under reducedpressure. The residue was diluted with water and extracted with Et₂O(3×20 mL). The combined organics were washed with HCl (1 M, 20 mL),water (20 mL), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated. The crude was used without further purification. MSm/z=310 [M+1]'. Calc'd for C₁₉H₁₉NO₃: 309.

To (R)-benzyl 1-oxo-1-phenylpent-4-en-2-ylcarbamate (2.13 g, 6.89 mmol)in THF (50 mL) at −78° C. under argon was added lithiumtri-sec-butylborohydride (20.7 ml, 20.7 mmol). Allowed the mixture tostir for 45 min. Quenched the reaction with saturated aqueous Rochelle'ssalt (50 mL) and the volatiles were removed in vacuo. The aqueousresidue was extracted with ether (3×50 mL). The ether was combined andwashed with brine (20 mL), dried over Na₂SO₄ and filtered. The filtratewas evaporated onto silica gel and purified via flash chromatography (0%to 20%; EtOAc in hexanes). MS m/z=334 [M+Na]⁺. Calc'd for C₁₉H₂₁NO₃:311.

Step 3: (4R,5R)-benzyl2,2-dimethyl-4-(2-oxoethyl)-5-phenyloxazolidine-3-carboxylate

To a solution of benzyl(1R,2R)-1-hydroxy-1-phenylpent-4-en-2-ylcarbamate (1.14 g, 3.66 mmol) inCH₂Cl₂ (50 mL) and 2,2-dimethoxypropane (15.0 ml, 122 mmol) was addedp-toluenesulfonic acid monohydrate (0.070 g, 0.366 mmol) and allowed tostir at room temperature overnight. The reaction was diluted with CH₂Cl₂(100 mL), washed with 9% Na₂CO₃ (20 mL), brine (20 mL), dried overNa₂SO₄, filtered and concentrated. MS m/z=352 [M+1]⁺. Calc'd forC₂₂H₂₅NO₃: 351.

To the crude (4R,5R)-benzyl4-allyl-2,2-dimethyl-5-phenyloxazolidine-3-carboxylate (1.29 g, 3.66mmol) in THF (50 mL) and water (20 mL) was added osmium tetroxide (0.45ml, 0.0180 mmol, 4%) solution. The reaction was stirred for 10 min,after which sodium periodate (3.91 g, 18.3 mmol) was added portion wiseover 1 hr. Stirring was continued for 2 h. Saturated aqueous Na₂S₂O₃ wasadded and the reaction was stirred for 15 min. The volatiles wereremoved in vacuo and the aqueous residue extracted with Et₂O (3×50 mL).The combined ether layers were washed with water (20 mL), brine (20 mL),dried over Na₂SO₄, filtered and concentrated. The crude residue wasevaporated onto silica gel and purified via flash chromatography (0% to20%; EtOAc in hexanes) to afford (4R,5R)-benzyl2,2-dimethyl-4-(2-oxoethyl)-5-phenyloxazolidine-3-carboxylate. MSm/z=354 [M+1]⁺. Calc'd for C₂₁H₂₃NO₄: 353.

Step 4: (4R,5R)-benzyl4-(2-(tert-butoxycarbonyl)ethyl)-2,2-spirocyclobutyl-5-phenyloxazolidine-3-carboxylate

A solution of (4R,5R)-benzyl2,2-dimethyl-4-(2-oxoethyl)-5-phenyloxazolidine-3-carboxylate (0.184 g,0.521 mmol) and(S)-6-ethyl-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-amine (0.226 g,1.04 mmol) were allowed to stir for 10 min in THF (5 mL) at RT. Sodiumtriacetoxyborohydride (0.166 g, 0.781 mmol) was added and the mixturewas allowed to stir for an additional 30 min. Di-tert-butyl dicarbonate(0.375 g, 1.72 mmol) was added and the mixture was stirred at RTovernight. The reaction was quenched with 5 mL aqueous Rochelle's salt,and stirred for 10 min. The volatiles were removed in vacuo and thecrude aqueous residue was extracted with CH₂Cl₂ (3×15 mL). The combinedorganics were washed with brine (10 mL), dried over Na₂SO₄ and filtered.The crude filtrate was evaporated onto silica gel and purified via flashchromatography (0% to 20%; EtOAc in hexanes). MS m/z=643[M+1]⁺. Calc'dfor C₃₉H₅₀N₂O₆: 642.

Step 5: Tert-butyl (3R,4R)-3-amino-4-hydroxy-4-phenylbutyl((S)-6-ethyl-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-yl)carbamate

To an argon purged solution of (4R,5R)-benzyl4-(2-(tert-butoxycarbonyl)ethyl)-2,2-spirocyclobutyl-5-phenyloxazolidine-3-carboxylate(0.324 g, 0.495 mmol) in EtOH was added palladium on carbon (10%)(0.0527 g, 0.0495 mmol). Hydrogen was bubbled through the mixture for 45min and the mixture was then purged with argon. The reaction wasfiltered through a 0.25 um filter. 3 Drops of HOAc was added and thereaction was stirred overnight at 0° C. The mixture was concentrated,taken up in CH₂Cl₂ and washed with 9% Na₂CO₃ (5 mL), brine (10 mL),dried over Na₂SO₄, filtered and concentrated. The crude residue was usedwithout further purification. MS m/z=481 [M+1]⁺. Calc'd for C₂₉H₄₀N₂O₄:480.

Step 6:1-cyclopentyl-N-((1R,2R)-4-((S)-6-ethyl-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-ylamino)-1-hydroxy-1-phenylbutan-2-O-6-oxo-5-(2-oxopyrrolidin-1-O-1,6-dihydropyridine-3-carboxamide

To1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxylicacid (0.0683 g, 0.235 mmol), HATU (0.134 g, 0.353 mmol), tert-butyl(3R,4R)-3-amino-4-hydroxy-4-phenylbutyl((S)-6-ethyl-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-yl)carbamate(0.113 g, 0.235 mmol) in CH₂Cl₂ (4 mL) was added diisopropylethylamine(0.123 ml, 0.705 mmol). The mixture was stirred at RT for 20 min.Anhydrous HCl in ether (1M, 15 mL) was added and the reaction wasallowed to stir for 5 h. The mixture was concentrated, and purified onan RP-HPLC to obtain the title compound. MS m/z=653[M+1]⁺. Calc'd forC₃₉H₄₈N₄O₅: 652

Example 170

1-cyclopentyl-N-((1R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl)amino)-1-((S)-hydroxy(phenyl)methyl)propyl)-6-oxo-5-(2-oxo-1-pyrrolidinyl)-1,6-dihydro-3-pyridinecarboxamide

The title compound was made by a method analogous to that described inExample 169. MS: 642 (M+H⁺).

Example 171

1-(furan-2-ylmethyl)-N-((2S,3R)-3-hydroxy-4-((S)-6-neopentyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamideStep 1: 2-Fluoro-5-neopentylpyridine

To a stirred, cooled (−78° C.) solution of(1S,5S)-9-methoxy-9-bora-bicyclo[3.3.1]nonane (260 ml, 260 mmol) in THF(200 ml) was added neopentylmagnesium chloride (260 ml, 260 mmol)drop-wise. The mixture slowly warmed to RT and stirred for 3 h. Thewhite solid was filtered off and washed thoroughly with pentane. Thefiltrate was concentrated to give the light yellow oil. This residue wasdiluted with p-dioxane (300 ml) and to this was added5-bromo-2-fluoropyridine (35.20 g, 200 mmol), (Ph₃P)₄Pd (9.7 g, 8.4mmol), and 5 N NaOH (168 ml, 838 mmol). The resulting reaction mixturewas heated at 95° C. in 16 h. The mixture was cooled and added 5 N HCl(168 ml) and the reaction was stirred for 1 h and extracted with ether(3×). The organic layers were washed with brine, dried over MgSO₄,concentrated and purified by ISCO (5% EtOAc/Hexanes) to give the lightyellow oil. MS (m+1): 168.2.

Step 2: (1-allylcyclobutoxy)(tert-butyl)dimethylsilane

To a 2 L three-necked round bottom flask was added cyclobutanone (12.47g, 178 mmol) and THF (1200 mL). The solution was cooled to −78° C.Allylmagnesium bromide, 1 M in ether (196 ml, 196 mmol) was added via anaddition funnel over 30 min. The reaction was allowed to stir for 30min. MeOH (30 mL) was added to the reaction and the cooling bath wasremoved. The solution was stirred for about 10 min, then HCl (0.5 M, 500mL) was added. The reaction was transferred to a separatory funnel andextracted with Ether (2×1 L). The organic extracts were dried over MgSO₄and concentrated in vacuo (Note: Volatile Product). The final ˜100 mL ofconcentrate were re-dissolved in 1 L of DCM, dried over MgSO₄ andfiltered. TEA (61.5 ml, 442 mmol) was added followed bytert-butyldimethylsilyl triflate (66.0 ml, 287 mmol). The reaction wascooled in the warming dry ice bath used earlier in the experiment. After30 min, the reaction was checked by TLC and found to be complete. HCl(0.5 M, 500 mL) was added to quench the reaction. The reaction layerswere separated and the aqueous layer extracted with 600 mL of ether. Thecombined organic layers were dried over MgSO₄ and concentrated in vacuo.The resulting oil was loaded onto a 600 mL Frit almost full of silicagel and purified, eluting with 1400 mL of hexane. The hexane filtratewas carefully concentrated in vacuo to give(1-allylcyclobutoxy)(tert-butyl)dimethylsilane, as a colorless liquidthat also contained residual hexane. The crude material was carried onwithout further purification.

Step 3: 3-(1-(tert-butyldimethylsilyloxy)cyclobutyl)propane-1,2-diol

To a 2 L round bottomed flask was added (1-allylcyclobutoxy)(tert-butyl)dimethylsilane (previous step) and H₂O/t-BuOH (1:1, 1 L).NMO (32.68 g, 279 mmol) was added to the mixture. After stirring for 5min the solution was found to be homogenous. Osmium tetroxide (1.00 g,3.93 mmol) was added and the reaction was stirred at RT. After 2 h, TLCrevealed the reaction to be complete. 500 mL of H₂O and sodium sulfite(19.5 g, 155 mmol) were added and the reaction was stirred for anotherhour. The aqueous solution was extracted with ether (2×1 L). Thecombined organics were concentrated in vacuo to give3-(1-(tert-butyldimethylsilyloxy)cyclobutyl)propane-1,2-diol, as a lightyellow oil. The oil contained some t-BuOH, but was carried forwardwithout further purification.

Step 4: 2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)acetaldehyde

To a 2 L round bottomed flask was added3-(1-(tert-butyldimethylsilyloxy)cyclobutyl)propane-1,2-diol (80.0 g,307 mmol) and THF/t-BuOH/H₂O (1:1:2, 2 L). Sodium periodate (120.15 g,562 mmol) was added and the reaction was stirred at RT. After additionthe solution became yellow and thickened. The stirrer was adjusted tomaintain stirring. After 1.5 h, the reaction is complete as monitored byTLC (10% EtOAc/Hexane). 300 mL H₂O was added to the reaction and theaqueous solution was extracted with ether (3×600 mL). The combinedorganics were dried over MgSO₄ and carefully concentrated in vacuo(Note: volatile product). The oil was re-dissolved in 200 mL of benzeneand azeotroped to remove any excess t-BuOH. The crude oil was adsorbedonto a plug of silica gel and chromatographed through a glass column,eluting with 3% EtOAc in hexane, to provide a golden oil afterconcentrating in vacuo (Note: volatile product). The oil was dissolvedin 200 mL of benzene and concentrated in vacuo. The mixture was furtherconcentrated to remove excess benzene to give2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)acetaldehyde (67.5 g, 296mmol, 96.2% yield). The title compound yielded contained some benzeneand was carried forward without further purification.

Step 5:2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)-1-(2-fluoro-5-neopentylpyridin-3-yl)ethanol

2,2,6,6-tetramethylpiperidine (13.0 ml, 76.5 mmol) was dissolved in 500ml THF and cooled to −78° C. Butyllithium (26.8 ml, 67.0 mmol) was addedover the period of 10 min and the reaction was allowed to warm up to 0°C. and kept there for 3 min. The mixture was cooled back to −78° C. anda solution of 2-fluoro-5-neopentylpyridine (8.000 g, 47.8 mmol) in 10 mlTHF was added over the period of 30 min. The mixture was stirred for 20min at the same temperature and a solution of2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)acetaldehyde (19.7 g, 86.1mmol) in 25 ml THF was added over the period of 20 min. The reaction wasstirred for 15 min at the same temperature and hydrolyzed with 200 ml ofH₂O. The mixture was allowed to warm up to room temp and extracted 2times with 1 L EtOAc (each). The combined organic extracts were driedover MgSO₄ and evaporated. The crude material was used without furtherpurification. MS found 396.2.

Step 6:(R/S)-6-neopentyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ol

2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)-1-(2-fluoro-5-neopentylpyridin-3-yl)ethanol(approx 48 mmol (est.)) was dissolved in 500 ml dry THF andtetrabutylammonium fluoride, 1.0 m in THF (50 ml, 50 mmol) was added atRT. The red solution was stirred for 15 min and filtered through a 600ml frit, almost filled all the way up with silica. The remainingmaterial was washed of the silica with 1 L dry THF. 300 ml Dry THF wasadded and sodium hydride (NaH) (4.00 g, 174 mmol) was added portion wiseat RT. The mixture was heated to 65° C. for 1 h. The reaction washydrolyzed with 50 ml H₂O at 0° C. and evaporated. The mixture wasextracted 3× with 300 ml EtOAc and dried over MgSO₄. The material wasre-dissolved in 1800 ml THF and treated with NaH (4.00 g, 174 mmol)again. This time no extensive bubbling was observed and the mixture washeated to 65° C. for 2 h. The mixture was cooled to 0° C. and hydrolyzedwith 50 ml H₂O and evaporated. The mixture was extracted with 300 mlEtOAc (each), dried over MgSO₄ and evaporated. The mixture was filteredthrough a plug of silica and used without further purification.

Step 7:6-neopentyl-2,2-spirocyclobutyl-2,3-dihydropyrano[2,3-b]pyridin-4-one

The product from step 6 (10.000 g, 38.3 mmol) was dissolved in 400 mlDCM and DMP (Dess Martin Reagent) (21.1 g, 49.7 mmol) and monosodiumhydrogen carbonate (14.5 g, 172 mmol) were added. The mixture wasstirred for 2 h and 50 ml MeOH was added. Stirring was continued for 30min and the mixture was filtrated and 100 ml NaOH (1 M, aq.) was addedto the filtrate. This mixture was extracted 3× with 400 ml EtOAc (each)dried over Mg504 and evaporated. Glass col. chrom. (30-50% EtOAc inhex.) gave the title compound (9.10 g, 35.1 mmol, 91.7% yield) as ayellow solid.

Step 8:(R)-6-neopentyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ol

Borane DMS complex (7.07 ml, 74.5 mmol) and(S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole(5.32 ml, 5.32 mmol) were dissolved in 500 ml of toluene and cooled to0° C. A solution of the product from Step 7 (13.80 g, 53.2 mmol) in 50ml toluene was added over the period of 3 h. 50 ml MeOH was added at thesame temperature and the mixture was warmed up to RT. After 30 min, 25ml (1 M) HCl (aq.) was added and stirring was continued for 1 h.

The mixture was neutralized with NaOH (1 M; aq.) and extracted 3 timeswith 350 ml EtOAc (each).

The combined organic extracts were dried over MgSO₄ and evaporated. Thecrude product was dissolved in 350 ml MeOH and 1.5 g Pd/C was added andstirring was continued under N₂ for 2 h. (See Org. Lett., 465-467(2001)) for borane amine complexes and cleavage with Pd). The mixturewas filtered and evaporated and used without further purification. MSfound: 262.1.

Step 9:(s)-4-azido-6-neopentyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine

Product from Step 8 (13.00 g, 49.74 mmol), diphenyl azidophosphate(16.08 ml, 74.61 mmol) and DBU (11.16 ml, 74.61 mmol) were dissolved in250 ml of toluene and stirred overnight. The mixture was filteredthrough a pad of silica (600 ml glass sintered frit filled all the waywith silica; wash with 15% EtOAc in Hex.) and evaporated. The crudeproduct was dissolved without further purification in the next step.

Step 10:(S)-6-neopentyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

Product from Step 9 (12.020 g, 42 mmol) was dissolved in 500 ml THF andcooled to −20° C. Lithium aluminum hydride (50 ml, 100 mmol) was addedand stirring was continued for 2.5 h at the same temperature. 15 g ofNa₂SO₄ decahydrate was added carefully and stirring of the reaction wascontinued for 20 min followed by warming the reaction up to RT. Themixture was filtered and purified via glass col. chromatography (10-15%MeOH in DCM): Product 1 (9.800 g, 38 mmol, 90% yield) as a yellow solid.MS found: 261.2.

Step 11: Tert-Butyl(2S,3R)-3-(tert-butyldimethylsilyloxy)-1-phenylpent-4-en-2-ylcarbamate

To a 250 mL round bottom flask containing tert-butyl(2S,3R)-3-hydroxy-1-phenylpent-4-en-2-ylcarbamate (3.080 g, 11 mmol) wasadded DCM (50 mL) and the mixture was allowed to stir at 23° C. for 2min. At this time, TEA (4.7 ml, 33 mmol) was added via syringe beforedropwise addition of tert-butyldimethylsilyl triflate (2.8 ml, 12 mmol).The reaction was allowed to stir for 4 h and then poured into saturatedammonium chloride. The aqueous layer was extracted with DCM (3×75 mL)and the combined organics were washed with brine and dried with sodiumsulfate. The solution was filtered and concentrated to provide 4.47 g ofa yellow solid. The material was taken on to the next step without anyfurther purification.

Step 12: tert-Butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-4-oxo-1-phenylbutan-2-ylcarbamate

To a 500 mL round bottom flask containing tert-butyl(2S,3R)-3-(tert-butyldimethylsilyloxy)-1-phenylpent-4-en-2-ylcarbamate(1.200 g, 3.06 mmol) was added DCM (30 mL) and the mixture was allowedto stir at −78° C. for 5 min. At this time, ozone was bubble through thereaction until a blue color appeared and then oxygen was bubbled throughthe reaction until it was clear. DMS (6.80 ml, 91.9 mmol) was added andthe reaction was allowed to warm to 23° C. and stirred for 4 h before itwas filtered through a plug of silica gel (elute with 10% EtOAc in DCM)and concentrated to afford a colorless oil (1.17 g).

Step 13: tert-Butyl(2S,3R)-3-(tert-butyldimethylsilyloxy)-4-((S)-6-neopentyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-ylcarbamate

To a 150 mL round bottom flask containing tert-butyl(25,35)-3-(tert-butyldimethylsilyloxy)-4-oxo-1-phenylbutan-2-ylcarbamate(1.9 g, 4.8 mmol) was added DCE (20 mL) and the mixture was allowed tostir at 23° C. for about 2 min. At this time, product from step 10(800.00 mg, 3.7 mmol) was added and Trimethyl orthoformate (4.1 ml, 37mmol) was added via a syringe. The reaction was allowed to stir for 20min. Sodium triacetoxyborohydride (2.3 g, 11 mmol) was added in oneportion. The reaction was allowed to stir for 30 min and then sodiumcarbonate was added (10%, 40 mL). The reaction was allowed to stir for 1h and then extracted with DCM (4×35 ml), the combined organics werewashed with brine and dried with sodium sulfate, filtered andconcentrated to give 3.0 g of colorless oil that was purified to a 120 gIsco column (20 to 35% EtOAc in hexanes) to give 1.740 g of a whitefoamy solid (tic: Rf=0.50 in 40% EtOAc in hexanes). MS m/z (M+1): 596.

Step 14:(2R,3S)-3-amino-1-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-4-phenylbutan-2-ol

tert-Butyl(2S,3R)-3-(tert-butyldimethylsilyloxy)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-ylcarbamate(1.52 g, 2.38 mmol) was dissolved in 3 ml dioxane and 4M HCl in dioxane(15.00 ml, 60.0 mmol) was added. The reaction was stirred over theweekend and the BOC group was removed but only approx. 30% deprotectionof the silyl group. The reaction was warmed up to 60° C. for 10 h andpurified on the HPLC. The material was free based with K₂CO₃ (10% inwater and extracted with EtOAc) and used in the next steps.

Step 15:1-(furan-2-ylmethyl)-N-((2S,3R)-3-hydroxy-4-((S)-6-neopentyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide

(2R,3S)-3-amino-1-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-4-phenylbutan-2-ol(0.020 g, 0.047 mmol),1-(furan-2-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.010g, 0.047 mmol), N-ethyl-N-isopropylpropan-2-amine (0.041 ml, 0.24 mmol)and HATU (0.018 g, 0.047 mmol) were dissolved in 1 ml DMF at room tempand the mixture was stirred for 1 h and 5 M HCL (aq) was added until theyellow color disappeared. The mixture was purified on the HPLC withoutfurther workup procedure. The title compound was obtained as anoff-white solid. MS (M+H):625.

The following compounds in Table 3 below, synthesized by a methodanalogous to that described in Example 105, Example 148 or Example 169,provide additional representative examples of Formulas I-III.

Mass Ex. found No. STRUCTURE (M + H+) MW 172N-((2S,3R)-4-((S)-7-ethyl-3,3-dimethyl- 655.3 654.8471,3,4,5-tetrahydrobenzo[c]oxepin-5-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-oxo-5-(2-oxopyrrolidin-1-yl)-3-(pyrrolidin-1- yl)cyclohexa-1,5-dienecarboxamide173 N-((2S,3R)-4-((S)-6-chloro-2,2- 659 659.223spirocyclobutyl-3,4-dihydro-2H-chromen-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 174 N-((2S,3R)-4-((S)-6-chloro-2,2-552 552.111 spirocyclobutyl-3,4-dihydro-2H-chromen-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclobutyl-5-oxopyrrolidine-3-carboxamide 175N-((2S,3RS)-1-((S)-6-bromo-2,2-spirocyclo- 669 1339.31butyl-3,4-dihydro-2H-chromen-4-ylamino)-2-hydroxy-5-methylhexan-3-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 176N-((2S,3RS)-4-((S)-6-bromo-2,2-spirocyclo- 711 1419.44butyl-3,4-dihydro-2H-chromen-4-ylamino)-3-hydroxy-1-cyclohexylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 1771-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 659 658.859spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-(thiophen-3-yl)butan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 1781-cyclopentyl-N-((2S,3RS)-4-((S)-6-ethyl-2,2- 659 1317.72spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-(thiophen-2-yl)butan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 179N-((2S,3RS)-4-((S)-6-bromo-2,2-dimethyl-3,4- 743 1483.44dihydro-2H-chromen-4-ylamino)-3-hydroxy-1-(naphthalen-1-yl)butan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 1801-cyclopentyl-N-((1S,2R)-3-((S)-6-ethyl-2,2- 639.4 638.804spirocyclobutylchroman-4-ylamino)-2- hydroxy-1-phenylpropyl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 1811-cyclobutyl-N-((1S,2R)-3-((S)-6-ethyl-2,2- 532.2 531.693spirocyclobutylchroman-4-ylamino)-2-hydroxy-1-phenylpropyl)-5-oxopyrrolidine-3- carboxamide 182N-((2S,3R)-4-((S)-6-bromo-2,2-dimethyl- 735.3 735.666chroman-4-ylamino)-1-(3,5-difluorophenyl)-3- 737.3hydroxybutan-2-yl)-1-cyclopentyl-5-(5- methylpyridin-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 183N-((2S,3R)-4-((S)-6-bromo-2,2-dimethyl- 723.1 723.45chroman-4-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-1-cyclopentyl-5-(5- methylpyridin-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 184N-((2S,3R)-4-((S)-6-bromo-2,2-dimethyl- 739.3 739.629chroman-4-ylamino)-1-(3,5-difluorophenyl)-3- 741.3hydroxybutan-2-yl)-1-cyclopentyl-5-(5-fluoropyridin-2-yl)-6-oxo-1,6-dihydropyridine- 3-carboxamide 185N-((2S,3R)-1-(3-cyanophenyl)-4-((S)-6-ethyl- 504.3 503.6392,2-spirocyclobutylchroman-4-ylamino)-3-hydroxybutan-2-yl)-tetrahydrofuran-2- carboxamide 186N-((2S,3R)-1-(3-cyanophenyl)-4-((S)-6-ethyl- 678.3 677.832,2-spirocyclobutylchroman-4-ylamino)-3-hydroxybutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 187N-((2S,3R)-1-(3-cyanophenyl)-4-((S)-6-ethyl- 672.4 671.8382,2-spirocyclobutylchroman-4-ylamino)-3-hydroxybutan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 188(S)-N-((2S,3R)-1-(3-cyanophenyl)-4-((S)-6- 571.4 570.73ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxybutan-2-yl)-1-cyclobutyl-5- oxopyrrolidine-3-carboxamide 189N-((2S,3R)-4-((S)-6-bromo-2,2-spirocyclo- 771.2 772.659butylchroman-4-ylamino)-3-hydroxy-1-(3- 773.1(trifluoromethyl)phenyl)butan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 190(E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 594.3 565.754pentylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxamide 191(RS)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 555.3 1109.45pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)chroman-3-carboxamide 192(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 506.3 505.655pentyllchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxopyrrolidine-2- carboxamide 193(S)-1-(2-fluorobenzyl)-N-((2S,3R)-4-((S)-6- 600.4 599.786ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)pyrrolidine-2- carboxamide 194N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 582.3 581.753pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxo-1-phenylpyrrolidine- 2-carboxamide 1951-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 574.3 573.773spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxopyrrolidine- 3-carboxamide 196N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 520.2 519.682pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-methyl-5-oxopyrrolidine- 3-carboxamide 1971-cyclobutyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 560.3 559.747spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxopyrrolidine- 3-carboxamide 198N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 562.3 561.762pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-isobutyl-5-oxopyrrolidine- 3-carboxamide 1991-cyclobutyl-N-((2S,3R)-1-(3,5-difluoro- 582.2 581.7phenyl)-4-((S)-6-ethyl-2,2-spirocyclobutyl-chroman-4-ylamino)-3-hydroxybutan-2-yl)-5- oxopyrrolidine-3-carboxamide200 (RS)-1-cyclopropyl-N-((2S,3R)-4-((S)-6-ethyl- 532.3 1063.392,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxopyrrolidine- 3-carboxamide 201(R/S)-1-cyclobutyl-N-((2S,3R)-4-((S)-6-ethyl- 546.3 1091.442,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxopyrrolidine- 3-carboxamide 202(S)-1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl- 560.3 1119.492,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxopyrrolidine- 3-carboxamide 2031-cyclopentyl-N-((2S,3R)-4-((S)-2-ethyl-5,5- 640.3 639.86dimethyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 204(R)-1-cyclobutyl-N-((2S,3R)-4-((S)-6-ethyl- 546.2 545.722,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxopyrrolidine- 3-carboxamide 205(S)-1-cyclobutyl-N-((2S,3R)-4-((S)-6-ethyl- 546.2 545.722,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxopyrrolidine- 3-carboxamide 2061-cyclopentyl-N-((2S,3R)-4-((S)-3,3-dimethyl- 597.2 596.7682,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 2071-cyclopentyl-N-((2S,3R)-1-(3,5-difluoro- 669.2 1397.61phenyl)-4-((S)-6-ethyl-2,2-spiro-(+/−)-tetrahydrofuranchroman-4-ylamino)-3-hydroxybutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 2081-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 663.3 1325.65spirotetrahydrofuranchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 2091-cyclopentyl-N-((2S,3R)-4-((S)-5,5-dimethyl- 682.3 681.9412-neopentyl-4,5,6,7-tetrahydrobenzo[d]thiazol-7-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 210(3S,4R)-1-cyclopentyl-N-((2S,3R)-4-((S)-6- 622.4 621.861ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4- phenylpyrrolidine-3-carboxamide 211N-((2S,3R)-4-((S)-6-ethyl-2,2-spirotetrahydro- 628.3 1255.56furanchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-4-(3-methylbenzoyl)morpholine-2-carboxamide 212N-((2S,3R)-1-(3,5-difluorophenyl)-4-((S)-6- 664.2 1327.52ethyl-2,2-spirotetrahydrofuranchroman-4-ylamino)-3-hydroxybutan-2-yl)-4-(3-methylbenzoyl)morpholine-2-carboxamide 2131-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 652.2 1303.61spirotetrahydrofuranchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(1H-pyrazol-1-yl)-1,6-dihydropyridine-3- carboxamide 2141-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 701.2 1401.75spirotetrahydrofuranchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-(1H-indol-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 215N-((2S,3R)-3-hydroxy-4-((S)-6-neopentyl-2,2- 522.7 521.698spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)- tetrahydrofuran-2-carboxamide216 1-cyclopentyl-N-((2S,3R)-4-((S)-3,4-dihydro- 655.4 654.8712H-2,2-spirocyclopentylthiochromen-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 2171-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 572.7 571.7824-((S)-2,2-spirocyclopentylthiochroman-4- ylamino)butan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 218N-((2S,3R)-4-((R)-6-ethyl-2,2-spirocyclo- 520.2 1039.36butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-1-methyl-6-oxopiperidine-3-carboxamide 2191,3-dicyclopentyl-N-((2S,3R)-4-((S)-6-ethyl- 643.5 642.882,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-oxo- hexahydropyrimidine-5-carboxamide 220(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 507 506.643butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-1-methyl-2-oxoimidazolidine-4-carboxamide 221(S)-N-((2S,3R)-4-((S)-6-bromo-2,2-spirocyclo- 558, 560 557.486butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-1-methyl-2-oxoimidazolidine-4-carboxamide 222(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 521 520.67butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-1,3-dimethyl-2-oxoimidazolidine-4-carboxamide 2231,3-dicyclobutyl-N-((2S,3R)-4-((S)-6-ethyl- 615 614.8262,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-oxo- hexahydropyrimidine-5-carboxamide 224N-((2S,3R)-4-((S)-6-ethyl-2,2spirocyclo- 591.5 590.804butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1,3-diisopropyl-2-oxo-hexahydropyrimidine-5-carboxamide 225N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 580 579.737butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-(1-oxoisoindolin-2- yl)cyclopropanecarboxamid 2261-cyclopentyl-N-((2S,3R)-3-hydroxy-4-((S)-6- 706.3 1411.79neopentyl-3,4-dihydro-(2,2-spirotetrahydro-furanyl)-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 2271-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 649.2 648.8684-((S)-2,2-spirocyclopentylthiochroman-4-ylamino)butan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 228N-((3S,4R)-5-((S)-6-bromo-2,2-dimethyl-3,4- 683.1 683.562dihydro-2H-chromen-4-ylamino)-1,1,1-trifluoro-4-hydroxypentan-3-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 2291-Cyclopentyl-6-oxo-5-(pyridin-2-yl)-N- 682.3 681.795((3S,4R)-1,1,1-trifluoro-4-hydroxy-5-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)pentan-3-yl)-1,6-dihydropyridine-3-carboxamide 2301-cyclopentyl-N-((1S,2R)-3-(((4S)-6-ethyl-2,2- 689.3 688.885dimethyl-1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-6-oxo-5-(2-oxo-1- pyrrolidinyl)-1,6-dihydro-3-pyridinecarboxamide 231 1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-657.4 656.887 dimethyl-3,4-dihydro-2H-thiochromen-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydro- pyridine-3-carboxamide 232(E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 584.4 583.744pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-2,3-dihydro-1H- benzo[b]azepine-4-carboxamide233 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 570.4 569.717butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-2,3-dihydro-1H- benzo[b]azepine-4-carboxamide234 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 584.6 583.744pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-9-fluoro-2,3-dihydro-1H- benzo[b]azepine-4-carboxamide235 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 570.3 569.717butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-9-fluoro-2,3-dihydro-1H- benzo[b]azepine-4-carboxamide236 (E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-dimethyl- 558.3 557.706chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-9-fluoro-2,3-dihydro-1H- benzo[b]azepine-4-carboxamide237 (E)-N-((2S,3R)-1-(3,5-difluorophenyl)-4-((S)- 594.4 593.6866-ethyl-2,2-dimethylchroman-4-ylamino)-3-hydroxybutan-2-yl)-9-fluoro-2,3-dihydro-1H-benzo[b]azepine-4-carboxamide 238(E)-7-bromo-N-((2S,3R)-4-((S)-6-ethyl-2,2- 632.5 630.623spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxamide 239(E)-7-bromo-N-((2S,3R)-4-((S)-6-ethyl-2,2- 646.6 644.65spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-methyl-2,3-dihydro-1H-benzo[b]azepine-4-carboxamide 2401-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 615.6 614.7824-((S)-2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo-furan-4-ylamino)butan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 241(E)-7-fluoro-N-((2S,3R)-3-hydroxy-1-phenyl- 532.2 531.6684-((S)-2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo-furan-4-ylamino)butan-2-yl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxamide 2421-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 631.6 630.8494-((S)-2,6,6-trimethyl-4,5,6,7-tetrahydro- benzo[b]thiophen-4-ylamino)butan-2-yl)-6- oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 2431-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 548.2 547.764-((S)-2,6,6-trimethyl-4,5,6,7-tetrahydro- benzo[b]thiophen-4-ylamino)butan-2-yl)-6- oxo-1,6-dihydropyridine-3-carboxamide244 1-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 532.2 531.6934-((S)-2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo-furan-4-ylamino)butan-2-yl)-6-oxo-1,6- dihydropyridine-3-carboxamide 245(E)-7-fluoro-N-((2S,3R)-3-hydroxy-1-phenyl- 548.3 547.7354-((S)-2,6,6-trimethyl-4,5,6,7-tetrahydro- benzo[b]thiophen-4-ylamino)butan-2-yl)-2,3-dihydro-1H-benzo[b]azepine-4-carboxamide 2461-cyclobutyl-N-((2S,3R)-3-hydroxy-1-phenyl- 524.2 1047.484-((S)-2,6,6-trimethyl-4,5,6,7-tetrahydro- benzo[b]thiophen-4-ylamino)butan-2- yl)-5-oxopyrrolidine-3-carboxamide 2471-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 625.3 624.8464-((S)-2,6,6-trimethyl-4,5,6,7-tetrahydro- benzo[b]thiophen-4-ylamino)butan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 248(E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 553.2 552.715butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-8,9-dihydro-7H-pyrido[2,3-b] azepine-6-carboxamide 249(E)-N-((2S,3R)-3-hydroxy-1-phenyl-4-((S)- 531.3 530.7332,6,6-trimethyl-4,5,6,7-tetrahydro-benzo[b]thiophen-4-ylamino)butan-2-yl)-8,9- dihydro-7H-pyrido[2,3-b]azepine-6- carboxamide 250 1-cyclopentyl-N-((2S,3R)-4-((S)-2-ethyl-6,6-645.6 644.876 dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide251 1-cyclopentyl-N-((2S,3R)-4-((S)-2-ethyl-6,6- 639.5 638.872dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 252N-((2S,3R)-1-(3-cyanophenyl)-3-hydroxy-4- 650.2 649.856((S)-2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ylamino)butan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 2531-cyclopentyl-N-((2S,3S)-4-((S)-6-ethyl-2,2- 661.2 660.811spirocyclobutylchroman-4-ylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 2541-cyclopentyl-N-((2S,3R)-1-(3,5-difluoro- 661.2 660.826phenyl)-3-hydroxy-4-((S)-2,6,6-trimethyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ylamino)butan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 255N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 621.3 620.79butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-isopropyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 2565-(2-cyanophenyl)-1-cyclopentyl-N-((2S,3R)- 714.2 713.9183-hydroxy-4-((S)-6-neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-1,6- dihydropyridine-3-carboxamide257 1-cyclopentyl-5-(2-fluorophenyl)-N-((2S,3R)- 707.2 706.8983-hydroxy-4-((S)-6-neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-1,6- dihydropyridine-3-carboxamide258 1-cyclopentyl-N-((2S,3R)-3-hydroxy-4-((S)-6- 678.3 677.885neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-5-(1H-pyrrol-2-yl)-1,6-dihydropyridine-3-carboxamide 2591-cyclopentyl-5-(furan-3-yl)-N-((2S,3R)-3- 679.2 678.869hydroxy-4-((S)-6-neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-1,6- dihydropyridine-3-carboxamide260 1-cyclopentyl-N-((2S,3R)-3-hydroxy-4-((S)-6- 696.3 695.924neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-5-(thiazol-2-yl)-1,6-dihydropyridine-3-carboxamide 2611-cyclopentyl-N-((2S,3R)-3-hydroxy-4-((S)-6- 691.3 690.884neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-5-(pyrazin-2-yl)-1,6-dihydropyridine-3-carboxamide 262N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 449.2 448.603butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)cyclopropanecarboxamide 2631-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 709.3 708.7744-((S)-6-(trifluoromethoxy)-2,2-spirocyclo-butylchroman-4-ylamino)butan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 2641-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 626.3 625.6844-((S)-6-(trifluoromethoxy)-2,2-spirocyclo-butylchroman-4-ylamino)butan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 265N-((2S,3R)-4-((S)-6-ethyl-2,2spirocyclo- 478.3 477.645butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)pyrrolidine-1-carboxamide 2661-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-7- 671.3 670.821fluoro-3,4-dihydro-2,2-spirocyclo- butylchromen-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 2671-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-7- 588.3 587.732fluoro-3,4-dihydro-2,2spirocyclobutyl-chromen-4-ylamino)-3-hydroxy-1-phenyl-butan-2-yl)-6-oxo-1,6-dihydropyridine-3- carboxamide 268N-((2S,3R)-4-((S)-6-ethyl-7-fluoro-3,4- 604.3 603.706dihydro-2,2-spirocyclobutylchromen-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-fluoro-3-(2-oxopyrrolidin-1-yl)benzamide 269N-((2S,3R)-4-((S)-6-acetyl-3,4-dihydro-2,2- 667.2 666.814spriocyclobutyl-chromen-4-ylamino)-3- hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 270N-((2S,3R)-4-((S)-6-acetyl-2,2-spirocyclo- 661.2 660.811butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 271N-((2S,3S)-4-((S)-6-bromo-3,4-dihydro-2,2- 705.2 704.662spirocyclobutylpyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 2721-cyclopentyl-N-((2S,3S)-3-hydroxy-4-((S)-6- 690.2 689.896neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 2731-cyclopentyl-N-((2S,3S)-3-hydroxy-4-((S)-6- 696.2 695.9neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 274N-((2S,3R)-4-((R)-6-bromo-3,4-dihydro-2,2- 706 704.662spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 275N-((2S,3R)-4-((S)-6-bromo-3,4-dihydro-2,2- 704.1 704.662spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 276(S)-N-((2S,3S)-3-hydroxy-4-((S)-6-neopentyl- 655.3 1309.693,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-4-(3-methylbenzoyl)morpholine-2-carboxamide and(R)-N-((2S,3S)-3-hydroxy-4-((S)-6-neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1- phenylbutan-2-yl)-4-(3-methylbenzoyl)morpholine-2-carboxamide 277N-((2S,3R)-4-((3R,4S)-6-bromo-3-hydroxy- 709 1311.582,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide and N-((2S,3R)-4-((3S,4R)-6-bromo-3-hydroxy-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 278N-((2S,3R)-1-(3-cyanophenyl)-3-hydroxy-4- 735.3 734.893((S)-6-morpholino-2,2-spirocyclobutyl-chroman-4-ylamino)butan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 279N-((2S,3R)-1-(3-cyanophenyl)-3-hydroxy-4- 729.3 728.889((S)-6-morpholino-2,2-spirocyclobutyl-chroman-4-ylamino)butan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 280N-((2R,3S)-1-((S)-6-bromo-2,2-dimethyl- 639 639.587chroman-4-ylamino)-2-hydroxyhex-5-yn-3-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 281N-((2S,3R)-1-(1-benzyl-1H-1,2,3-triazol-4-yl)- 734 733.9094-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxybutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 282N-((2R,3S)-1-((S)-6-bromo-2,2-dimethyl- 705 705.69chroman-4-ylamino)-2-hydroxy-5-phenylpentan-3-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 283N-((2S,3R)-1-(1-tert-butyl-1H-1,2,3-triazol-4- 700 699.892yl)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxybutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 284N-((2R,3S)-1-((S)-6-bromo-2,2-dimethyl- 641 641.603chroman-4-ylamino)-2-hydroxyhex-5-en-3-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 285N-((2S,3R)-4-((S)-6-cyano-2,2-dimethyl- 668 667.753chroman-4-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 2861-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 636 635.805spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(1H-pyrazol-1-yl)-1,6-dihydropyridine-3- carboxamide 287N-((2S,3R)-1-(3-cyanophenyl)-4-((S)-2,2- 704 703.883spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxybutan-2-yl)-1-cyclopentyl-6-oxo-5-(1H-pyrazol-1-yl)-1,6-dihydropyridine-3- carboxamide 288N-((2R,3S)-1-((S)-6-bromo-2,2-dimethyl- 633 633.583chroman-4-ylamino)-2-hydroxyhex-5-yn-3-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6- dihydropyridine-3-carboxamide289 (S)-methyl 4-((2R,3S)-3-(1-cyclopentyl-2-oxo- 719 718.7943-(2-oxopyrrolidin-1-yl)-1,2-dihydropyridine-5-carboxamido)-4-(3,5-difluorophenyl)-2-hydroxybutylamino)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromene-6-carboxylate 2901-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spiro- 626.3 625.766cyclobutyl-3,4-dihydro-2H-pyrano[2,3- b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 2911-cyclopentyl-N-((2S,3R)-4-((R)-2,2-spiro- 626.3 625.766cyclobutyl-3,4-dihydro-2H-pyrano[2,3- c]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 2921-cyclobutyl-N-((2S,3R)-4-((R)-2,2-spirocyclo- 519.2 1037.31butyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5- oxopyrrolidine-3-carboxamide293 1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spiro- 626.3 625.766cyclobutyl-3,4-dihydro-2H-pyrano[2,3- c]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 294(S)-1-cyclobutyl-N-((2S,3R)-4-((S)-2,2-spiro- 519.2 518.654cyclobutyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ylamino)-3-hydroxy-1-phenyl-butan-2-yl)-5-oxopyrrolidine-3-carboxamide 295(R)-1-cyclobutyl-N-((2S,3R)-4-((S)-2,2-spiro- 519.3 518.654cyclobutyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ylamino)-3-hydroxy-1-phenyl-butan-2-yl)-5-oxopyrrolidine-3-carboxamide 2961-cyclopentyl-N-((2S,3R)-4-((R)-2,2-spiro- 688.3 687.759cyclobutyl-6-(trifluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 2971-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spiro- 688.3 687.759cyclobutyl-6-(trifluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 2981-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spiro- 694.2 693.763cyclobutyl-6-(trifluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 299N-((2S,3R)-4-((S)-6-chloro-2,2-spirocyclo- 660.2 660.211butyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 300N-((2S,3R)-4-((S)-6-chloro-2,2-spirocyclo- 654.2 654.207butyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6- dihydropyridine-3-carboxamide301 N-((2S,3R)-4-((S)-6-chloro-2,2-spirocyclo- 664.2 664.218butyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-5-((S)-3-fluoropyrrolidin-1-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 302(S)-N-((2S,3R)-4-((S)-6-chloro-2,2-spirocyclo- 553.2 553.099butyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclobutyl-5-oxopyrrolidine-3-carboxamide 303N-((2S,3R)-4-((R)-6-chloro-2,2-spirocyclo- 660.2 660.211butyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 304N-((2S,3R)-4-((S)-6-chloro-2,2-spirocyclo- 666.2 666.239butyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-(thiophen-3-yl)butan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 3051-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spiro- 690.3 689.896cyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 3061-cyclopentyl-N-((2S,3R)-4-(2,2-spirocyclo- 625 624.778butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 3071-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 654.3 653.819spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 3081-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 648.3 647.815spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 3091,3-dicyclobutyl-N-((2S,3R)-4-((S)-6-ethyl- 616.3 615.8142,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-oxo-hexahydropyrimidine- 5-carboxamide 310N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neo- 615.3 614.782pentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-((R)-tetrahydrofuran-3-yl)-1,6-dihydropyridine-3-carboxamide 3111-cyclopentyl-5-(3,3-difluorocyclopentyl)-N- 718.3 1433.82((2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3- b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6- dihydropyridine-3-carboxamide 312N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neo- 641.2 640.845pentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-(thiophen-2-ylmethyl)-1,6- dihydropyridine-3-carboxamide 3131-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spiro- 613.3 612.81cyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine- 3-carboxamide 3141-cyclopentyl-5-(3,3-difluorocyclopentyl)-N- 718.3 1349.66((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 315N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 573.2 572.7023,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-((R)-tetrahydrofuran-3-yl)-1,6- dihydropyridine-3-carboxamide316 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 583.2 582.6973,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)- 1-(furan-2-ylmethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide 317N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 599.2 598.7643,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-(thiophen-2-ylmethyl)-1,6- dihydropyridine-3-carboxamide 318(S)-N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6- 536.2 535.681neopentyl-3,4-dihydro-2H-pyrano[2,3- b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxo-tetrahydrofuran-2- carboxamide 3191-cyclopentyl-N-((2S,3R)-3-hydroxy-4-((S)-6- 690.3 689.896isopentyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 3201-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spiro- 695.4 694.912cyclobutyl-6-neopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 3211-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spiro- 612.4 611.822cyclobutyl-6-neopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6- oxo-1,6-dihydropyridine-3-carboxamide 3221-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spiro- 693.3 692.775cyclobutyl-6-(trifluoromethyl)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide323 1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spiro- 598.3 609.685cyclobutyl-6-(trifluoromethyl)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 324(S)-N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6- 546.3 545.599(trifluoromethyl)chroman-4-ylamino)-3- hydroxy-1-phenylbutan-2-yl)-6-oxopiperidine-2-carboxamide 325(S)-N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6- 548.3 547.735neopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxopiperidine-2- carboxamide 3261-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spiro- 687.3 686.771cyclobutyl-6-(trifluoromethyl)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 3271-cyclopentyl-N-((2S,3R)-1-(3,5-difluoro- 726.4 725.876phenyl)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxybutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 328N-((2S,3R)-1-(3-cyanophenyl)-4-((S)-2,2- 715.4 714.906spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-butan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 329N-((2S,3R)-4-((S)-6-chloro-2,2-spirocyclo- 752.3 752.351butyl-7-(morpholinomethyl)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6- dihydropyridine-3-carboxamide330 N-((2S,3R)-4-((S)-6-chloro-2,2-spirocyclo- 750.3 750.379butyl-7-(piperidinomethyl)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6- dihydropyridine-3-carboxamide331 N-((2S,3R)-4-((S)-6-chloro-2,2-spirocyclo- 738.3 738.324butyl-7-morpholinochroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 332(S)-N-((2S,3R)-1-(3-cyanophenyl)-4-((S)-2,2- 622.3 621.778spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy- butan-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide 333N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 489 488.668pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)cyclopent-1-enecarboxamide 334N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 567 566.694pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-oxo-2H-chromene-3- carboxamide 3351-cyclopentyl-N-((2S,3R)-4-((2S,4S)-6-ethyl-2- 671 1341.69(methoxymethyl)-2-methylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydro- pyridine-3-carboxamide and1-cyclopentyl-N- ((2S,3R)-4-((2R,4S)-6-ethyl-2-(methoxymethyl)-2-methylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 3361-cyclopentyl-N-((2S,3R)-4-((2R,4S)-6-ethyl- 665 1329.682-(methoxymethyl)-2-methylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide and1-cyclopentyl-N-((2S,3R)-4- ((2S,4S)-6-ethyl-2-(methoxymethyl)-2-methylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 3371-cyclopentyl-N-((2S,3R)-4-((2R,4S)-6-ethyl- 671 670.8462-(methoxymethyl)-2-methylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 3381-cyclopentyl-N-((2S,3R)-4-((2S,4S)-6-ethyl-2- 671 670.846(methoxymethyl)-2-methylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 3391-cyclopentyl-N-((2S,3R)-4-((2R,4S)-6-ethyl- 665 664.8422-(methoxymethyl)-2-methylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 3401-cyclopentyl-N-((2S,3R)-4-((2S,4S)-6-ethyl-2- 665 664.842(methoxymethyl)-2-methylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 3411-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 635 634.816dimethylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 3421-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 669.3 1337.66spirotetrahydrofuranylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 3431-cyclopentyl-N-((2S,3R)-4-((S)-2-cyclo- 642.3 641.808propyl-6,6-dimethyl-4,5,6,7-tetrahydro-benzo[d]oxazol-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide 3441-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 626.3 625.8094-((S)-3,7,7-trimethyl-5,6,7,8-tetrahydro-quinolin-5-ylamino)butan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 3451-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 677.3 676.853spirotetrahydropyran-4-ylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 3461-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-(R)- 669.3 668.832,2-spirotetrahydrofuranylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 3471-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-(S)- 669.3 668.832,2-spirotetrahydrofuranylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 3481-cyclopentyl-N-((2S,3R)-3-hydroxy-4-((S)-3- 632.3 631.817methyl-7,7-spirocyclobutyl-5,6,7,8-tetrahydro-quinolin-5-ylamino)-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 3491-cyclopentyl-N-((2S,3R)-1-(3,5-difluoro- 668.3 667.797phenyl)-3-hydroxy-4-((S)-3-methyl-7,7-spirocyclobutyl-5,6,7,8-tetrahydroquinolin-5-ylamino)butan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 3501-allyl-N-((2S,3R)-1-(3-allylphenyl)-4-((S)-6- 659.3 658.838ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxybutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 3511-allyl-N-((2S,3R)-1-(3-allylphenyl)-4-((S)-6- 660.2; 660.649ethyl-2,2-spirocyclobutylchroman-4-ylamino)- 662.23-hydroxybutan-2-yl)-5-bromo-6-oxo-1,6- dihydropyridine-3-carboxamide352 1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 685.3 684.876spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-(1H-indol-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 3531-acetyl-5-(cyclohexylmethyl)-N-((2S,3R)-4- 644.3 2575.63((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2- yl)piperidine-3-carboxamide 3545-(cyclohexylmethyl)-N-((2S,3R)-4-((S)-6- 680.3 2719.85ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-(methylsulfonyl)piperidine-3-carboxamide 355N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 491.3 490.684chroman-4-ylamino)-3-hydroxy-1-phenylbutan- 2-yl)cyclohexanecarboxamide356 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 525.3 1049.4chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-phenylcyclopropanecarboxamide 357N-((2S,3R)-1-(1-acetylpiperidin-3-yl)-4-((S)-6- 702.3 701.904ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxybutan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine- 3-carboxamide 358N-((2S,3R)-4-((S)-6-bromo-2,2-spirocyclo- 704 704.662butylchroman-4-ylamino)-3-hydroxy-1-(pyridin-3-yl)butan-2-yl)-1-cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine- 3-carboxamide 3591-cyano-N-((2S,3R)-4-((S)-6-ethyl-2,2-spiro- 474.2 473.613cyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)cyclopropanecarboxamide 360(S)-1-(cyclopentanecarbonyl)-N-((2S,3R)-4- 562.3 561.762((S)-6-ethyl-2,2-dimethylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)pyrrolidine-3- carboxamide 3611-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 642.2 1283.624-(-2,6,6-trimethyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolin-8-ylamino)butan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 3621-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 642.3 641.8084-((S)-2,6,6-trimethyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolin-8-ylamino)butan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 3631-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 642.3 641.8084-((R)-2,6,6-trimethyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolin-8-ylamino)butan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6- dihydropyridine-3-carboxamide 364(R)-3-acetyl-N-((2S,3S)-3-hydroxy-4-((S)-6- 581.2 580.79neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)thiazolidine-2-carboxamide 365(S)-3-acetyl-N-((2S,3S)-3-hydroxy-4-((S)-6- 581.2 580.79neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)thiazolidine-2-carboxamide 366N-((2S,3R)-1-(3-cyanophenyl)-4-((S)-6-ethyl- 594.3 1187.452,2-spirocyclobutylchroman-4-ylamino)-3-hydroxybutan-2-yl)-5-oxo-1-(pyridin-2- yl)pyrrolidine-3-carboxamide 3671-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 655.4 654.847spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-morpholino-6-oxo-1,6-dihydropyridine-3-carboxamide 3681-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 657.4 656.838spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-((S)-3- fluoropyrrolidin-1-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 369N-((2S,3R)-4-((S)-6-chloro-2,2-spirocyclo- 663.3 663.23butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-5-((S)-3-fluoropyrrolidin-1-yl)-6-oxo-1,6- dihydropyridine-3-carboxamide 370N-((2S,3R)-4-((S)-2,2-spirocyclobutylchroman- 629.3 628.7844-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-5-((S)-3-fluoropyrrolidin-1-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 3711-cyclopentyl-5-((S)-3-fluoropyrrolidin-1-yl)- 697.3 696.782N-((2S,3R)-3-hydroxy-1-phenyl-4-((S)-6-(trifluoromethyl)-2,2-spirocyclobutylchroman-4-ylamino)butan-2-yl)-6-oxo-1,6- dihydropyridine-3-carboxamide 3721-cyclopentyl-5-((S)-3-fluoropyrrolidin-1-yl)- 631.4 1261.61N-(-4-(2,7,7-trimethyl-5,6,7,8-tetrahydro-quinazolin-5-ylamino)butan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide 3731-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 627.4 1253.594-(2,7,7-trimethyl-5,6,7,8-tetrahydroquinazolin-5-ylamino)butan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3- carboxamide 3741-cyclopentyl-N-((2S,3R)-3-hydroxy-1-phenyl- 621.3 1241.594-(2,7,7-trimethyl-5,6,7,8-tetrahydroquinazolin-5-ylamino)butan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide 375(S)-1-cyclobutyl-N-((2S,3R)-3-hydroxy-1- 520.3 1039.37phenyl-4-(2,7,7-trimethyl-5,6,7,8-tetrahydroquinazolin-5-ylamino)butan-2-yl)-5-oxopyrrolidine-3-carboxamide 3761-cyclopentyl-5-(3,3-difluoropyrrolidin-1-yl)- 675.3 674.828N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl-chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3- carboxamide 377N-((2S,3R)-1-(3-cyanophenyl)-4-((S)-6-ethyl- 700.3 699.8382,2-spirocyclobutylchroman-4-ylamino)-3-hydroxybutan-2-yl)-1-cyclopentyl-5-(3,3-difluoropyrrolidin-1-yl)-6-oxo-1,6- dihydropyridine-3-carboxamide 378N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 586.3 585.741chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridine-3-carboxamide 379N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 572.3 571.714chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-((R)-tetrahydrofuran-3-yl)-1,6-dihydropyridine-3-carboxamide 3805-bromo-N-((2S,3R)-4-((S)-6-ethyl-2,2-spiro- 652.2 650.61cyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-((R)-tetrahydro-furan-3-yl)-1,6-dihydropyridine-3-carboxamide 381N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 582.3 581.709chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-(furan-2-ylmethyl)-6- oxo-1,6-dihydropyridine-3-carboxamide 382N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 598.3 597.776chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-(thiophen-2-ylmethyl)-1,6- dihydropyridine-3-carboxamide383 N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 649.3 648.8chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1-((R)-tetrahydro-furan-3-yl)-1,6-dihydropyridine-3-carboxamide 384N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 659.3 658.81chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-((S)-3-fluoropyrrolidin-1-yl)-6-oxo-1-((R)-tetrahydrofuran-3-yl)-1,6-dihydropyridine- 3-carboxamide 385N-((2S,3R)-4-((S)-6-cyano-2,2-(spirotetra- 660.2 1319.57hydrofuran-3-yl)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 386N-((2S,3R)-4-((S)-6-cyano-2,2-(spirotetra- 662.2 1323.51hydrofuran-3-yl)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1-((R)-tetrahydrofuran-3-yl)-1,6-dihydropyridine-3-carboxamide 387N-((2S,3R)-4-((S)-6-cyano-2,2-(spirotetra- 585.2 1169.34hydrofuran-3-yl)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-((R)-tetrahydrofuran-3-yl)-1,6-dihydropyridine-3- carboxamide 388N-((2S,3R)-4-((S)-2,2-(spirotetrahydrofuran-3- 635.2 1269.55yl)chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 389N-((2S,3R)-4-((S)-6-bromo-2,2-spirotetra- 713 1415.32hydrofuranylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3- carboxamide 390(R)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 554 553.743pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1,2,3,4-tetrahydroquinoline- 3-carboxamide 391(S)-N-((2S,3R)-4-(6-ethyl-2,2-spirocyclo- 554 553.743pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1,2,3,4-tetrahydroquinoline- 3-carboxamide 392N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 568 1135.54pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-1-methyl-1,2,3,4- tetrahydroquinoline-3-carboxamide393 4-acetyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spiro- 596 595.736cyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4H-benzo[b][1,4]oxazine-2- carboxamide 394(R)-4-benzoyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 678 677.813spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-3,4-di-hydro-2H-benzo[b][1,4]oxazine-2-carboxamide 395N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 574 1147.41pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide 396(R)-4-acetyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 616 615.742spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-3,4-di-hydro-2H-benzo[b][1,4]oxazine-2-carboxamide 397(S)-4-acetyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 616 615.742spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-3,4-di-hydro-2H-benzo[b][1,4]oxazine-2-carboxamide 398(R)-4-benzoyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 678 677.813spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-3,4-di-hydro-2H-benzo[b][1,4]oxazine-2-carboxamide 399(S)-4-benzoyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 678 677.813spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-3,4-di-hydro-2H-benzo[b][1,4]oxazine-2-carboxamide 400(R)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 644 643.795pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-4-isobutyryl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2- carboxamide 401(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 644 643.795pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-4-isobutyryl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2- carboxamide 402(R)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 644 643.795pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-4-isobutyryl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2- carboxamide 403(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 644 643.795pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-4-isobutyryl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2- carboxamide 404N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 508 1015.34pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2-carboxamide 4054-benzoyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 612 1223.56spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2- carboxamide 4064-acetyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spiro- 550 1099.42cyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2-carboxamide 407(R)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 522 521.698pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-methylmorpholine-2- carboxamide 408(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 522 521.698pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-methylmorpholine-2- carboxamide 409(R)-4-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl- 576 575.7892,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2- carboxamide 410(S)-4-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl- 576 575.7892,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2- carboxamide 411(R)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 630 629.769butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-4-isobutyryl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2- carboxamide 412(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 630 629.769butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-4-isobutyryl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2- carboxamide 413(R)-4-benzoyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 664 663.786spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-3,4-di-hydro-2H-benzo[b][1,4]oxazine-2-carboxamide 414(S)-4-benzoyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 664 663.786spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-3,4-di-hydro-2H-benzo[b][1,4]oxazine-2-carboxamide 415N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 574 1147.41chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide 416(R)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 630 629.769butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-4-isobutyryl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2- carboxamide 417(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 630 629.769butylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-fluoro-4-isobutyryl-3,4-dihydro-2H-benzo[b][1,4]oxazine-2- carboxamide 418(R)-4-benzoyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 664 663.786spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-3,4-di-hydro-2H-benzo[b][1,4]oxazine-2-carboxamide 419(R)-4-acetyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 602 601.715spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-3,4-di-hydro-2H-benzo[b][1,4]oxazine-2-carboxamide 420 tert-butyl3-(((2S,3R)-4-((S)-6-ethyl-2,2- 608 1215.57spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)morph- oline-4-carboxylate 421(S)-4-acetyl-N-((2S,3R)-4-((S)-6-ethyl-2,2- 602 601.715spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-7-fluoro-3,4-di-hydro-2H-benzo[b][1,4]oxazine-2-carboxamide 422(R)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 508 507.671pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-3-carboxamide 423(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 508 507.671pentylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-3-carboxamide 424(S)-4-(cyclopentanecarbonyl)-N-((2S,3R)-4- 590 589.772((S)-6-ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2- yl)morpholine-2-carboxamide 425N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 612 1223.56chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-(4-methylbenzoyl)morpholine-2- carboxamide 426N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 612 1223.56butylchroman-4-ylamino)-3-hydroxy-1-phenyl-butan-2-yl)-4-(3-methylbenzoyl)morpholine-2- carboxamide 4274-(cyclohexanecarbonyl)-N-((2S,3R)-4-((S)-6- 604 1207.6ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2- carboxamide 4284-(3-chlorobenzoyl)-N-((2S,3R)-4-((S)-6-ethyl- 632 1264.392,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2- carboxamide 429N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 612 1223.56chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-(2-methylbenzoyl)morpholine-2- carboxamide 4304-(4-chlorobenzoyl)-N-((2S,3R)-4-((S)-6-ethyl- 632 1264.392,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2- carboxamide 431(R)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 678 677.813butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-7-fluoro-4-(3-methylbenzoyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-2-carboxamide 432(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 678 677.813butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-7-fluoro-4-(3-methylbenzoyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-2-carboxamide 433N-((2S,3R)-1-(3-cyanophenyl)-4-((S)-6-ethyl- 637 1273.582,2-spirocyclobutylchroman-4-ylamino)-3- hydroxybutan-2-yl)-4-(3-methylbenzoyl)morpholine-2-carboxamide 434(R)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 610 609.806butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-1-(3-methylbenzoyl)piperidine-3-carboxamide 435(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 610 609.806butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-1-(3-methylbenzoyl)piperidine-3-carboxamide 4364-(3,5-dimethylbenzoyl)-N-((2S,3R)-4-((S)-6- 626 1251.61ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2- carboxamide 437N-((2S,3R)-1-(3-allylphenyl)-4-((S)-6-ethyl- 664 1327.712,2-spirocyclobutylchroman-4-ylamino)-3- hydroxybutan-2-yl)-4-(3-vinylbenzoyl)morpholine-2-carboxamide 4384-(cycloheptanecarbonyl)-N-((2S,3R)-4-((S)-6- 618 1235.65ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine- 2-carboxamide 439N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 606 1211.54chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-(tetrahydro-2H-pyran-4- carbonyl)morpholine-2-carboxamide 440N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 613 1225.53chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-(2-methylpicolinoyl)morpholine-2- carboxamide 441N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 613 1225.53chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-4-(3-methylnicotinoyl)morpholine-2- carboxamide 442N-((2S,3R)-3-hydroxy-4-((S)-6-neopentyl-2,2- 655 1309.69spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-4-(3-methylbenzoyl)morpholine-2-carboxamide 443N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 750 1499.36chroman-4-ylamino)-3-hydroxy-1-(3-vinyl-phenyl)butan-2-yl)-4-(4-iodobenzoyl) morpholine-2-carboxamide 4444-(3-bromobenzoyl)-N-((2S,3R)-4-((S)-6-ethyl- 678 1353.32,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2- carboxamide 445(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 724 1447.29butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-4-(3-iodobenzoyl)morpholine-2-carboxamide 4464-(3-phenylbenzoyl)-N-((2S,3R)-4-((S)-6- 674 1347.7ethyl-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2- carboxamide 447N⁴-benzyl-N²-((2S,3R)-4-((S)-6-ethyl-2,2- 627 1253.59spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-2,4- dicarboxamide 448N-((2S,3R)-4-(3-(trifluoromethyl)benzyl- 570 1139.24amino)-3-hydroxy-1-phenylbutan-2-yl)-4-(3-methylbenzoyl)morpholine-2-carboxamide 449N²-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 641 1281.64butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-N⁴-((S)-1-phenylethyl)morpholine-2,4-dicarboxamide 450N²-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 641 1281.64butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-N⁴-((R)-1-phenylethyl)morpholine-2,4-dicarboxamide 451(S)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclo- 607 1213.52butylchroman-4-ylamino)-3-hydroxy-1- phenylbutan-2-yl)-4-(morpholine-4-carbonyl)morpholine-2-carboxamide 452 methyl3-(2-(((2S,3R)-4-((S)-6-ethyl-2,2-spiro- 656 488.668cyclobutylchroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)morpholine- 4-carbonyl)benzoate 4531,1-dimethylethyl 2-((((1S,2R)-3-(((4S)-6- 610 609.827ethyl-3,4-dihydrospiro[chromene-2,1′- cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)amino)carbonyl)-4- thiomorpholinecarboxylate 454N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl- 494 493.644chroman-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)morpholine-4-carboxamide 455 1′-cyclopentyl-N-((1S,2R)-2-hydroxy-1-703 702.77 (phenylmethyl)-3-(((4S)-6-((trifluoro-methyl)oxy)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 4561′-cyclopentyl-N-((1S,2R)-3-(((4S)-6-ethyl-7- 665 664.818fluoro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 4571′-cyclopentyl-N-((1S,2R)-2-hydroxy-3-(((4S)- 704 703.8796-(4-morpholinyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-(phenyl-methyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′- bipyridine-5′-carboxamide

Example 458(2S)—N-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-((4-propyl-1H-1,2,3-triazol-1-yl)acetyl)-2-morpholinecarboxamideand(2R)—N-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-((4-propyl-1H-1,2,3-triazol-1-yl)acetyl)-2-morpholinecarboxamideStep 1: 2-Benzyl 4-tert-butyl morpholine-2,4-dicarboxylate

In a 500-mL round-bottom flask, the4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (5.0 g, 22 mmol) wasdissolved in DMF (75 mL). Benzyl bromide (3.6 ml, 30 mmol) was added viasyringe, followed by potassium carbonate (4.8 g, 35 mmol). The sides ofthe glass were rinsed down with dmf (25 mL), and an air condenser wasaffixed, the reaction mixture was heated at 80° C. in an oil bath for 14h. The reaction was cooled to ambient temperature and concentrated. Theresidue was transferred to a separatory funnel with 60% ether-hexane(300 mL), and the organic layer was extracted with water (75 mL),half-saturated brine (30 mL), and saturated brine (30 mL), then wasdried over sodium sulfate and concentrated. The residue was purifiedthrough silica gel (500 mL) using 20% to 30% EtOAc-hexane to afford thetitle compound (6.81 g, 21 mmol). MS m/z 266 (M+1-isobutylene).

Step 2: Benzyl morpholine-2-carboxylate

In a 500-mL round-bottom flask, 2-benzyl 4-tert-butylmorpholine-2,4-dicarboxylate (7.94 g, 25 mmol) was dissolved in DCM (200mL). It was then cooled to 0° C. TFA (15 ml, 198 mmol) was added viapipet, and the solution was allowed to warm naturally to ambienttemperature in the ice bath, whereupon it was stirred for 14 h. Themixture was concentrated to afford the title compound (50% by weightwith the remainder assumed to be TFA, 10.86 g, 24 mmol). MS m/z 222(M+1).

Step 3: Benzyl 4-(2-chloroacetyl)morpholine-2-carboxylate

In a 100-mL round-bottom flask, the benzyl morpholine-2-carboxylate(50%, 1.00 g, 2.3 mmol) as the crude tfa salt was taken up indichloromethane (8 mL), resulting in a white suspension.N-Ethyl-N-isopropylpropan-2-amine (1.4 ml, 7.9 mmol) was added, and thesolid dissolved. The solution was cooled to 0 deg, and 2-chloroacetylchloride (0.20 ml, 2.5 mmol) was added. The reaction mixture was allowedto warm naturally to ambient temperature where it was stirred for 14 h.The reaction mixture was diluted with DCM (75 mL), and the organic layerwas extracted with dilute sodium bicarbonate (2×7 mL) then withhalf-saturated brine (7 mL), then was dried over sodium sulfate. Theresidue was purified through silica gel (100 mL) which had beendeactivated with TEA (10 mL) using 90% EtOAc-hexane, affording the titlecompound (474 mg, 1.6 mmol). MS m/z 298 (M+1).

Step 4: Benzyl 4-(2-azidoacetyl)morpholine-2-carboxylate

In a 25-mL round-bottom flask, the benzyl4-(2-chloroacetyl)morpholine-2-carboxylate (0.262 g, 0.88 mmol) wasdissolved in dmf (4 mL). Sodium azide (0.066 g, 1.0 mmol) was added, andthe flask was placed in a 60 deg oil bath overnight. The reaction wasconcentrated, and the residue was taken up in 80% ether-hexane (60 mL)and the organic layer was extracted with dilute sodium bicarbonate (2×7mL) then with saturated brine (7 mL), then was dried over magnesiumsulfate, filtered, and concentrated. The residue was purified throughsilica gel (50 mL) which had been deactivated with TEA (5 mL) using 60%EtOAc-hexane to afford the title compound (230 mg, 0.76 mmol). MS m/z305 (M+1).

Step 5: Benzyl4-(2-(4-propyl-1H-1,2,3-triazol-1-yl)acetyl)morpholine-2-carboxylate

In a sealable vessel, benzyl 4-(2-azidoacetyl)morpholine-2-carboxylate(0.096 g, 0.32 mmol) was suspended in t-BuOH (1 mL) and water (1 mL) wasadded. An aqueous solution of sodium ascorbate (1.0 M, 0.032 ml, 0.032mmol) and an aqueous solution of copper(II) sulfate pentahydrate (0.30M, 0.079 ml, 0.024 mmol) were added, followed by pent-1-yne (0.040 ml,0.41 mmol). The vessel was sealed and placed in a 65 deg oil bath,whereupon the mixture was stirred for 14 h. The reaction mixture wascooled to RT, taken up in EtOAc (60 mL), and the organic layer wasextracted with dilute sodium bicarbonate (5 mL), dilute brine (5 mL),and saturated brine (5 mL), then was dried over sodium sulfate andconcentrated. The residue was purified through silica gel (25 mL)eluting with EtOAc, affording the title compound (105 mg, 0.28 mmol). MSm/z 373 (M+1).

Step 6:4-(2-(4-propyl-1H-1,2,3-triazol-1-yl)acetyl)morpholine-2-carboxylic acid

In a 25-mL RBF, benzyl4-(2-(4-propyl-1H-1,2,3-triazol-1-yl)acetyl)morpholine-2-carboxylate(0.105 g, 0.282 mmol) was taken up in MeOH (1.0 mL). Lithium hydroxidehydrate (0.0130 g, 0.310 mmol) was added as a solution in water (1.0mL). The mixture was stirred at ambient temperature for 14 h, thenconcentrated, and used crude in the subsequent step. MS m/z 283 (M+1).

Step 7: (2S)—N-((1S,2R)-3-(((4S)-6-Bromo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-((4-propyl-1H-1,2,3-triazol-1-yl)acetyl)-2-morpholinecarboxamide;and(2R)—N-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-((4-propyl-1H-1,2,3-triazol-1-yl)acetyl)-2-morpholinecarboxamide

In a 15-mL RBF, the4-(2-(4-propyl-1H-1,2,3-triazol-1-yl)acetyl)morpholine-2-carboxylic acid(0.034 g, 0.11 mmol) as the crude lithium salt and(2R,3S)-3-amino-1-((S)-6-bromo-2,2-dimethylchroman-4-ylamino)-4-phenylbutan-2-ol(0.046 g, 0.11 mmol) were taken up in DMF (1.5 mL). When the solids haddissolved, HATU (0.041 g, 0.11 mmol) was added. After 14 h, the reactionwas concentrated, and the residue was taken up in EtOAc (60 mL) and theorganic layer was extracted with water (5 mL), dried over sodium sulfateand concentrated. The residue was purified through silica gel (15 mL)which had been deactivated with TEA (2.0 mL) eluting with 4% MeOH-EtOAc,to afford the title compound as a 1:1 mixture of diastereomers. MS m/z695/697 (M+1).

Example 459(2R)-4-(Azidoacetyl)-N-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-morpholinecarboxamide;and(2S)-4-(azidoacetyl)-N-(1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-morpholinecarboxamideStep 1: 4-(2-Azidoacetyl)morpholine-2-carboxylic acid

Benzyl 4-(2-azidoacetyl)morpholine-2-carboxylate (Example 458, Step 4,0.048 g, 0.16 mmol) converted to the lithium salt of4-(2-azidoacetyl)morpholine-2-carboxylic acid (37 mg, 0.16 mmol) usingthe procedure described in Example 458, Step 6. MS m/z 215 (M+1).

Step 2:(2R)-4-(Azidoacetyl)-N-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-morpholinecarboxamide;and(2S)-4-(azidoacetyl)-N-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-morpholinecarboxamide(AMG 2027495)

In a 15-mL RBF, 4-(2-azidoacetyl)morpholine-2-carboxylic acid as thecrude lithium salt (0.033 g, 0.15 mmol) was converted to the titlecompound using the procedure described in Example 458, Step 7. MS m/z627/629 (M+1).

Example 460(3,5)-N˜3˜-((1S,2R)-3-(((4S)-6-Ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-5-phenyl-N˜1˜-((1R)-1-phenylethyl)-1,3-piperidinedicarboxamideStep 1. Methyl1-(((R)-1-phenylethyl)carbamoyl)-5-phenylpiperidine-3-carboxylate

To a 150 mL RBF was added methyl 5-phenylpiperidine-3-carboxylate (0.10g, 0.46 mmol), toluene (15 mL), and (R)-(+)-1-phenylethyl isocyanate(0.065 ml, 0.46 mmol), and the mixture was stirred at RT. After 16hours, the crude reaction was adsorbed onto a plug of silica gel andchromatographed through a Redi-Sep® pre-packed silica gel column (12 g),eluting with 0% to 100% EtOAc in hexane, to provide a mixture of methyl1-(((R)-1-phenylethyl)carbamoyl)-5-phenylpiperidine-3-carboxylate and1,3-bis((R)-1-phenylethyl)urea as a colorless solid MS m/z: 367.1 (M+1).

Step 2: 1-(((R)-1-phenylethyl)carbamoyl)-5-phenylpiperidine-3-carboxylicacid

To a 150 mL RBF was added the mixture from step 1 (150 mg), THF:MeOH(3:1, 15 mL), and LiOH, 1M (1.00 ml, 1.0 mmol) and the mixture wasstirred at RT. After 2 hours, the reaction was neutralized and extractedwith EtOAc (3×20 mL). The combined organic layers were concentrated invacuo to give a white solid. The material was carried forward withoutfurther purification.

Step 3:(3,5)-N˜3˜-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-5-phenyl-N˜1˜-((1R)-1-phenylethyl)-1,3-piperidinedicarboxamide

The crude material (79 mg) from step 2 was coupled using HATU andpurified by reverse-phase preparative HPLC (Shimadzu) on a PhenomenexGemini column (5 micron, C18, 110 Å, 150×30 mm) eluting at 45 mL/minwith a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v TFA) in water(0.1% TFA) over 20 minutes to give(3,5)-N˜3˜-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-5-phenyl-N˜1˜-((1R)-1-phenylethyl)-1,3-piperidinedicarboxamideas a colorless solid. MS m/z: 715.3 (M+1).

Example 461(2R)-4-((3,3-dimethyl-1-piperidinyl)carbonyl)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-morpholinecarboxamide;and(2S)-4-((3,3-dimethyl-1-piperidinyl)carbonyl)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-morpholinecarboxamideStep 1: Benzyl4-(3,3-dimethylpiperidine-1-carbonyl)morpholine-2-carboxylate

In a dry 25-mL RBF, phosgene (0.25 ml, 0.47 mmol) was dissolved in DCM(2 mL) and the solution was cooled to 0° C. A solution of benzylmorpholine-2-carboxylate (50%, 0.070 g, 0.16 mmol, Example 458, Step 2)and N-ethyl-N-isopropylpropan-2-amine (0.041 ml, 0.24 mmol) in DCM (2mL) was added. The solution was stirred at 0° C. for 4 h, and the icebath was removed, and the mixture stirred at RT for 1 hour. The reactionmixture was concentrated, and the residue dissolved in DCM (2 mL), andN-ethyl-N-isopropylpropan-2-amine (0.041 ml, 0.24 mmol) and3,3-dimethylpiperidine (0.022 g, 0.20 mmol) were added by syringe. After14 h, the reaction mixture was concentrated. The residue was purifiedthrough silica gel (20 mL) using 50% EtOAc-hexane to afford the titlecompound. MS m/z 361 (M+1).

Step 2: 4-(3,3-Dimethylpiperidine-1-carbonyl)morpholine-2-carboxylicacid

In a 15-mL RBF, the benzyl4-(3,3-dimethylpiperidine-1-carbonyl)morpholine-2-carboxylate (0.036 g,0.100 mmol) was converted to4-(3,3-Dimethylpiperidine-1-carbonyl)morpholine-2-carboxylic acid usingthe procedure described in Example 458, Step 6, to afford the titlecompound as the crude lithium salt.

Step 3:(2R)-4-((3,3-Dimethyl-1-piperidinyl)carbonyl)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-morpholinecarboxamide;and(2S)-4-((3,3-dimethyl-1-piperidinyl)carbonyl)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-morpholinecarboxamide

In a 25-mL RBF, the4-(3,3-dimethylpiperidine-1-carbonyl)morpholine-2-carboxylic acid as thecrude lithium salt (0.039 g, 0.099 mmol) was coupled with(S)-6-ethyl-2,2-spirocyclobutyl-4-amine (0.038 g, 0.099 mmol) accordingto the procedure described in Example 458, Step 7 to afford the titlecompound. MS m/z 633 (M+1).

Example 4621-cyclopentyl-N-((1S,2R)-3-(((1R)-3,3-dimethyl-7-(methyloxy)-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamideStep 1: 6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one

6-methoxy-1-tetralone (3.00 g, 17 mmol) was added to RBF followed by THF(20 mL). Sodium hydride (1.1 ml, 43 mmol) was added and the reaction wasstirred at RT under nitrogen for 20 minutes. Gas evolution was observed.Iodomethane (2.7 ml, 43 mmol) was added via syringe and the reaction wasstirred at RT overnight. The reaction was quenched with water (25 mL)and extracted with EtOAc (3×100 mL). The combined organic layers werewashed with brine, dried over MgSO₄ and filtered. The solvent wasevaporated and the residue was purified by column chromatography (0-10%EtOAc/Hexane to provide the title compound as a white solid (2.77 g, 80%yield). MS m/z: 205.2 (M+1).

Step 2: 4-bromo-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one

To a mixture of 6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one(3.30 g, 16.2 mmol) and 1-bromopyrrolidine-2,5-dione (2.88 g, 16.2 mmol)in 50 mL of CCl₄, was added AIBN (0.265 g, 1.62 mmol). The mixture washeated to reflux for three hours. The reaction was cooled to RT and thereaction was quenched with water (25 mL) and extracted with EtOAc (3×100mL). The combined organic layers were washed with brine, dried overMgSO₄ and filtered. The solvent was evaporated and the residue waspurified by column chromatography (0-50% EtOAc/Hexane to provide thetitle compound as a white solid (3.92 g, 86% yield). MS m/z: 284.2(M+1).

Step 3: 4-azido-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one

4-Bromo-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one (3.9 g,14 mmol) was added to DMF (10 mL) followed by azidosodium (3.6 g, 55mmol). The mixture was heated to 60° C. overnight. The reaction wascooled to RT and quenched with water (25 mL). The aqueous layer wasextracted with Et₂O (3×100 mL). The combined organic layers were washedwith brine, dried over MgSO₄ and filtered. The solvent was evaporatedand the residue was purified by column chromatography (0-50%EtOAc/Hexane to provide the title compound as a white solid (3.05 g, 90%yield). MS m/z: 268.2 (M+Na).

Step 4: 4-amino-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one

To a solution of4-azido-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one (2.50 g,10.2 mmol) in EtOH (100 mL) at RT was added palladium on carbon (1.08 g,10.2 mmol) in two portions. A hydrogen balloon was affixed to thereaction flask and the head space above the solvent was purged with H₂.After 5 hours, the solution was filtered through a plug of celite andconcentrated to provide the crude product as an oil. The residue waspurified by column chromatography 100% DCM to 50% (10% MeOH/DCM/1%NH₄OH) to provide the title compound as a yellow oil (2.04 g, 91%yield). MS m/z: 220.2 (M+1).

Step 5:4-((2R,3S)-3-amino-2-hydroxy-4-phenylbutylamino)-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one

Tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (2.4 g, 9.1mmol) and 4-amino-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one(2.00 g, 9.1 mmol) were added to IPA (30 mL) and heated to 80° C. After16 hours, the reaction was cooled to RT and concentrated in vaccuo. Theresidue was purified by column chromatography using 0-10% MeOH/DCM. Theprotected amine was take up in 14 mL of 4N HCl in MeOH and stirred atRT. After 3 hours, the reaction mixture was concentrated to afford thedesired product as the HCl salt (0.95 g 55% yield). MS m/z: 283.2 (M+1).

Step 6:1′-cyclopentyl-N-((1S,2R)-3-(((1R)-3,3-dimethyl-7-(methyloxy)-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide

1-Cyclopentyl-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxylicacid (0.076 g, 0.26 mmol) was added to a vial followed by DMF (1 mL).HATU (0.15 g, 0.39 mmol) was added and the mixture was stirred for 5minutes.4-((2R,3S)-3-amino-2-hydroxy-4-phenylbutylamino)-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one(0.100 g, 0.26 mmol) was added followed by the addition ofdiisopropylethylamine (0.18 ml, 1.0 mmol). Reaction was allowed to stirat RT. After 2 hours, reaction the crude reaction mixture was purifiedusing the Gilson. The solvent was evaporated to provide the titlecompound as a white solid. MS m/z: 655.6 (M+1).

Example 4631-cyclopentyl-N-((1S,2R)-3-(((1R)-3,3-dimethyl-7-(methyloxy)-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-6-oxo-5-(2-oxo-1-pyrrolidinyl)-1,6-dihydro-3-pyridinecarboxamide

1-cyclopentyl-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxylicacid (0.0743 g, 0.261 mmol) was added to a vial followed by DMF (1 mL).HATU (0.15 g, 0.39 mmol) was added and the mixture was stirred for 5minutes.4-((2R,3S)-3-amino-2-hydroxy-4-phenylbutylamino)-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one(0.100 g, 0.26 mmol) was added followed by the addition ofdiisopropylethylamine (0.18 ml, 1.0 mmol). Reaction was allowed to stirat RT. After 2 hours, reaction the crude reaction mixture was purifiedusing the Gilson. The solvent was evaporated to provide the titlecompound as a white solid. MS m/z: 649.6 (M+1).

Ex. Mass No. Compound Name Found 464(2S)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4- 612dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 465(2R)-N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- 540dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)tetrahydro-2-furancarboxamide 466(2S)-N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- 540dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)tetrahydro-2-furancarboxamide 467N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- 540dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)tetrahydro-3-furancarboxamide 468(2S)-N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- 540dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)tetrahydro-2-furancarboxamide 469(3S)-3-((1R)-2-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- 450.3dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-hydroxyethyl)-3,4-dihydro-1(2H)- isoquinolinone 470N-((1S,2R)-3-(((4′R)-6′-bromo-3′,4′-dihydro-1′H- 697spiro[cyclobutane-1,2′-quinolin]-4′-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-1′-cyclopentyl-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 471N-((1S,2R)-3-(((4′S)-6′-bromo-3′,4′-dihydro-1′H- 697spiro[cyclobutane-1,2′-quinolin]-4′-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-1′-cyclopentyl-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 472N-((1S,2R)-1-((4-fluorophenyl)methyl)-3-(((4S)-7- 523.2fluoro-6-(1H-pyrazol-1-yl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2- hydroxypropyl)cyclopropanecarboxamide473 N-((1S,2R)-1-((4-fluorophenyl)methyl)-3-(((4S)-7- 537fluoro-6-(1H-pyrazol-1-yl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2- hydroxypropyl)cyclobutanecarboxamide 474(2R)-N-((1S)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro- 591.22H-chromen-4-yl)amino)-2-oxo-1-(phenyl-methyl)propyl)-4-(1-piperidinylcarbonyl)-2- morpholinecarboxamide 475(2S)-N-((1S)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro- 591.22H-chromen-4-yl)amino)-2-oxo-1- (phenylmethyl)propyl)-4-(1-piperidinylcarbonyl)-2-morpholinecarboxamide 4761′-cyclopentyl-N-((1S,2R)-3-((4S)-3,4- 619dihydrospiro[chromene-2,1′-cyclobutan]-4-ylamino)-2-hydroxy-1-(phenylmethyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 4771′-cyclopentyl-N-((1S)-1-((1R)-2-(((4S)-6-ethyl-3,4- 609.3dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-hydroxyethyl)-3-pentyn-1-yl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 478N-((1S,2S,3S)-3-(((4S)-6-bromo-2,2-dimethyl-3,4- 699.1dihydro-2H-chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)butyl)-1′-cyclopentyl-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 479N-((1S,2R,3S)-3-(((4S)-6-bromo-2,2-dimethyl-3,4- 699.1dihydro-2H-chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)butyl)-1′-cyclopentyl-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 480N-((1S,2S,3R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4- 699.1dihydro-2H-chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)butyl)-1′-cyclopentyl-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 481N-((1S,2R)-3-(((4R)-6-bromo-2,2-dimethyl-1,2,3,4- 686tetrahydro-4-quinolinyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-1′-cyclopentyl-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 482N-((1S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-1,2,3,4- 685tetrahydro-4-quinolinyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-1′-cyclopentyl-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 4831′-cyclopentyl-N-((1S,2R)-3-(((4S)-6-ethyl-3,4- 629.3dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-((propyloxy)methyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 484(2R)-N-((1S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4- 593dihydro-2H-chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-(1-piperidinylcarbonyl)-2- morpholinecarboxamide485 (2S)-N-((1S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4- 593dihydro-2H-chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-(1-piperidinylcarbonyl)-2- morpholinecarboxamide486 N-((1S,2R)-3-(((4R)-6-bromo-2,2-dimethyl-1,2,3,4- 686tetrahydro-4-quinolinyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-1′-cyclopentyl-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 487N-((1S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-1,2,3,4- 686tetrahydro-4-quinolinyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-1′-cyclopentyl-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 4881′-cyclopentyl-N-((1S,2R)-3-(((4R)-6-(2,2- 676dimethylpropyl)-2,2-dimethyl-1,2,3,4-tetrahydro-4-quinolinyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 4891′-cyclopentyl-N-((1S,2R)-3-(((4S)-6-(2,2- 676dimethylpropyl)-2,2-dimethyl-1,2,3,4-tetrahydro-4-quinolinyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 490(2S)-N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy- 622.23-(((5′S)-3′-methyl-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 491(2R)-N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy- 622.23-(((5′S)-3′-methyl-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 492(2S)-N-((1S,2R)-1-((3,5-difluorophenyl)methyl)-2- 633.2hydroxy-3-(((5′S)-3′-methyl-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 493(2R)-N-((1S,2R)-1-((3,5-difluorophenyl)methyl)-2- 633.2hydroxy-3-(((5′S)-3′-methyl-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 494(2S)-N-((1S,2R)-2-hydroxy-3-(((5′S)-3′-methyl-5′,8′- 597.2dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)-1-(phenylmethyl)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 495(2R)-N-((1S,2R)-2-hydroxy-3-(((5′S)-3′-methyl-5′,8′- 597.2dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)-1-(phenylmethyl)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 496(2S)-N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy- 610.23-(((5S)-3,7,7-trimethyl-5,6,7,8-tetrahydro-5-quinolinyl)amino)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 497(2R)-N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy- 610.23-(((5S)-3,7,7-trimethyl-5,6,7,8-tetrahydro-5-quinolinyl)amino)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 498(2S)-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((5S)- 585.23,7,7-trimethyl-5,6,7,8-tetrahydro-5-quino-linyl)amino)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 499(2R)-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((5S)- 585.23,7,7-trimethyl-5,6,7,8-tetrahydro-5-quinolinyl)amino)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 5001′-cyclopentyl-N-((1S,2R)-3-(((4S)-6-ethyl-3,4- 668.3dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-((2-methyl-1,3-thiazol-4-yl)methyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 501N-((1S,2R)-3-(((4S)-2-(2,2-dimethylpropyl)-6,6- 655.3dimethyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-1′-(1-methylethyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 502N-((1S,2R)-2-hydroxy-3-(((5′S)-3′-methyl-5′,8′-dihydro- 478.26′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)-1-(phenylmethyl)propyl)tetrahydro-2H-pyran-4- carboxamide 503N-((1S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3- 502.2(((5S)-3,7,7-trimethyl-5,6,7,8-tetrahydro-5-quinolinyl)amino)propyl)tetrahydro-2H-pyran-4- carboxamide 504N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((5S)-3,7,7- 466.2trimethyl-5,6,7,8-tetrahydro-5-quinolinyl)amino)propyl)tetrahydro-2H-pyran-4- carboxamide 5051′-cyclopentyl-N-((1S,2R)-3-(((1S)-3,3-dimethyl-7-((2- 692.6(methyloxy)ethyl)amino)-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 5071′-cyclopentyl-N-((1R,2R)-3-(((1S)-3,3-dimethyl-7-((2- 692.6(methyloxy)ethyl)amino)-4-oxo-1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 508N-((1S,2R)-3-(((4S)-2-ethyl-4,7-dihydro-5H-spiro[1- 625.2benzothiophene-6,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-1′-(1-methylethyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 509(3R)-N-((1S,2R)-1-((3,5-difluorophenyl)methyl)-2- 500.2hydroxy-3-(((5′S)-3′-methyl-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)propyl)tetrahydro-3-furancarboxamide 510N-((1S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3- 514.2(((5′S)-3′-methyl-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)propyl)tetrahydro-2H-pyran- 4-carboxamide 511(2R)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4- 612dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 5121′-cyclopentyl-N-((1S,2R)-3-(((3R)-2,2-dimethyl-2,3- 594.2dihydrofuro[2,3-b]pyridin-3-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 5131′-cyclopentyl-N-((1S,2R)-3-(((3S)-2,2-dimethyl-2,3- 594.2dihydrofuro[2,3-b]pyridin-3-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2′-oxo-1,2′-dihydro-2,3′-bipyridine-5′-carboxamide 514(2S)-N-((1S,2R)-3-(((4S)-2-ethyl-6,6-dimethyl-4,5,6,7- 604.2tetrahydro-1-benzothien-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 515(2R)-N-((1S,2R)-3-(((4S)-2-ethyl-6,6-dimethyl-4,5,6,7- 604.2tetrahydro-1-benzothien-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-((3-methylphenyl)carbonyl)-2-morpholinecarboxamide 516 (2R)-N-((1S,2R)-3-(((1S)-3,3-dimethyl-7-((3S)-537.3 tetrahydro-3-furanyloxy)-1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1-(phenyl-methyl)propyl)-5-oxotetrahydro-2-furancarboxamide 517(2S)-N-((1S,2R)-3-(((1S)-3,3-dimethyl-7-((3S)- 537.3tetrahydro-3-furanyloxy)-1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1-(phenyl-methyl)propyl)-5-oxotetrahydro-2-furancarboxamide 5181-cyclopentyl-N-((1S,2R)-3-(((1S)-3,3-dimethyl-7-((3S)- 614.3tetrahydro-3-furanyloxy)-1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1- (phenylmethyl)propyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide 5191′-cyclopentyl-N-((1S,2R)-3-(((1S)-3,3-dimethyl-7- 691.3((3S)-tetrahydro-3-furanyloxy)-1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 5201′-cyclopentyl-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)- 7043-(((4′S)-6′-((2S)-tetrahydro-2-furanylmethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′- carboxamide521 (2S)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4- 621dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-(((2S)-2-methyl-4-morpholinyl)carbonyl)-2-morpholinecarboxamide 5221-cyclopentyl-N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethyl- 669.3propyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- (M − 28 +b]pyridin]-4′-yl)amino)-2-hydroxy-1-(phenyl- H)methyl)propyl)-6-oxo-5-(tetrahydro-2H-pyran-2-yl)-1,6-dihydro-3-pyridinecarboxamide 523(3S)-1-cyclobutyl-N-((1S,2R)-3-(((4S)-2-ethyl-6,6- 538.2dimethyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-5-oxo-3- pyrrolidinecarboxamide 524(3S)-1-cyclobutyl-N-((1S,2R)-2-hydroxy-3-(((4S)-6-(4- 602.9morpholinyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-(phenylmethyl)propyl)-5-oxo-3-pyrrolidinecarboxamide 5251′-cyclopentyl-N-((1S,2R)-3-(((4S)-6-ethyl-3,4- 654.3dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(1,3-thiazol-4-ylmethyl)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 526(2S)-N-((1S,2R)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)- 663.43,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-(phenylmethyl)propyl)-4-(tetrahydro-2H-pyran-4-ylcarbonyl)-2-morpholinecarboxamide 527(3R,5S)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4- 686.3dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-1-((3-methylphenyl)carbonyl)-5-phenyl-3- piperidinecarboxamide 528(2S)-N-((1S,2R)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)- 550.33,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-(phenylmethyl)propyl)-5-oxotetrahydro-2- furancarboxamide529 (2R)-N-((1S,2R)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)- 550.33,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-(phenylmethyl)propyl)-5-oxotetrahydro-2- furancarboxamide520 (2R)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4- 592dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-((3R)-tetrahydro-3-furanylcarbonyl)-2-morpholinecarboxamide 531(2S)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4- 605dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-(1-piperidinylcarbonyl)-2-morpholinecarboxamide 532(2R)-N-((1S,2R)-3-(((4′S)-6′-ethyl-3′,4′- 494dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-5-oxotetrahydro-2-furancarboxamide 533(2S)-N-((1S,2R)-3-(((4′S)-6′-ethyl-3′,4′- 494dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-5-oxotetrahydro-2-furancarboxamide 534(2R)-N-((1S,2R)-3-(((4′S)-6′-chloro-3′,4′- 500, 502dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-5-oxotetrahydro-2-furancarboxamide 535(2S)-N-((1S,2R)-3-(((4′S)-6′-chloro-3′,4′- 500, 502dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-5-oxotetrahydro-2-furancarboxamide 536N-((1S,2R)-1-((3-cyano-5-fluorophenyl)methyl)-3- 690.3(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)-1′-cyclopentyl-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′- carboxamide 537(2S)-N-((1S,2R)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)- 664.43,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-(phenylmethyl)propyl)-4-(4-morpholinylcarbonyl)-2-morpholinecarboxamide 538N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-((2S,4S)- 609.33,4,4′,5′-tetrahydrospiro[chromene-2,3′-furan]-4-ylamino)propyl)-1′-(1-methylethyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 539N-((1S,2R)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4- 678.2dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-(phenylmethyl)propyl)-1′-(1-methylethyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide 540(2S)-N-((1S,2R)-3-(((4S)-6-ethyl-3,4- 628dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-4-((3-(methyloxy)phenyl)carbonyl)-2-morpholinecarboxamide 541(2S)-4-((3-cyanophenyl)carbonyl)-N-((1S,2R)-3-(((4S)- 6236-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2- morpholinecarboxamide 542(2R)-N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- 536.2dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-5-oxotetrahydro-2-furancarboxamide

While the examples described above provide processes for synthesizingcompounds of Formulas I-III, other methods may be utilized to preparesuch compounds. Methods involving the use of protecting groups may beused. Particularly, if one or more functional groups, for example,carboxy, hydroxy, amino, or mercapto groups, are or need to be protectedin preparing the compounds of the invention, because they are notintended to take part in a specific reaction or chemical transformation,various known conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

The protecting groups may already be present in precursors and shouldprotect the functional groups concerned against unwanted secondaryreactions, such as acylations, etherifications, esterifications,oxidations, solvolysis, and similar reactions. It is a characteristic ofprotecting groups that they readily lend themselves, i.e. withoutundesired secondary reactions, to removal, typically accomplished bysolvolysis, reduction, photolysis or other methods of removal such as byenzyme activity, under conditions analogous to physiological conditions.It should also be appreciated that the protecting groups should not bepresent in the end-products, unless present as part of a pro-drug. Thespecialist knows, or can easily establish, which protecting groups aresuitable with the reactions described herein.

The protection of functional groups by protecting groups, the protectinggroups themselves, and their removal reactions (commonly referred to as“deprotection”) are described herein, as well as in various publicationsor in standard reference works, such as J. F. W. McOmie, ProtectiveGroups in Organic Chemistry, Plenum Press, London and New York (1973),in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York(1981), in The Peptides, Volume 3, E. Gross and J. Meienhofer editors,Academic Press, London and New York (1981), in Methoden der OrganischenChemie (Methods of Organic Chemistry), Houben Weyl, 4^(th) edition,Volume 15/1, Georg Thieme Verlag, Stuttgart (1974), in H.-D. Jakubke andH. Jescheit, Aminosauren, Peptide, Proteine (Amino Acids, Peptides,Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel (1982),and in Jochen Lehmann, Chemie der Kohlenhydrate: Monosaccharide andDerivate (Chemistry of Carbohydrates: Monosaccharides and Derivatives),Georg Thieme Verlag, Stuttgart (1974).

Synthetic procedures may also be carried out where functional groups ofstarting compounds, which are not intended to take part in the reaction,may be present in unprotected form without the added step of protectingthat group by, for example, one or more of the protecting groupsmentioned above or taught in the references above.

Salts of a compound of the invention having a salt-forming group may beprepared in a conventional manner or manner known to persons skilled inthe art. For example, acid addition salts of compounds of the inventionmay be obtained by treatment with an acid or with a suitable anionexchange reagent. A salt with two acid molecules (for example adihalogenide) may also be converted into a salt with one acid moleculeper compound (for example a monohalogenide); this may be done by heatingto a melt, or for example by heating as a solid under a high vacuum atelevated temperature, for example from 50° C. to 170° C., one moleculeof the acid being expelled per molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Exemplarysalt forms and their preparation are described herein in the Definitionsection of the application.

All synthetic procedures described herein can be carried out under knownreaction conditions, advantageously under those described herein, eitherin the absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H⁺ form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphaticethers, e.g., Et₂O and ethylene glycol dimethylether or cyclic ethers,e.g., THF; liquid aromatic hydrocarbons, including benzene, toluene andxylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n- andt-butanol; nitriles including CH₃CN; halogenated hydrocarbons, includingCH₂Cl₂, CHCl₃ and CCl₄; acid amides including DMF; sulfoxides, includingDMSO; bases, including heterocyclic nitrogen bases, e.g. pyridine;carboxylic acids, including lower alkanecarboxylic acids, e.g., AcOH;inorganic acids including HCl, HBr, HF, H₂SO₄ and the like; carboxylicacid anhydrides, including lower alkane acid anhydrides, e.g., aceticanhydride; cyclic, linear, or branched hydrocarbons, includingcyclohexane, hexane, pentane, isopentane and the like, and mixtures ofthese solvents, such as purely organic solvent combinations, orwater-containing solvent combinations e.g., aqueous solutions. Thesesolvents and solvent mixtures may also be used in “working-up” thereaction as well as in processing the reaction and/or isolating thereaction product(s), such as in chromatography.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or not, prior to obtaining the finally desired compound.Structures resulting from carrying out steps from a transient startingmaterial, structures resulting from divergence from the describedmethod(s) at any stage, and structures forming starting materials underthe reaction conditions are all “intermediates” included in theinvention. Further, structures produced by using starting materials inthe form of a reactive derivative or salt, or produced by a compoundobtainable by means of the process according to the invention andstructures resulting from processing the compounds of the invention insitu are also within the scope of the invention.

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise the subject of this invention. Inselect embodiments, such starting materials are used and reactionconditions so selected as to obtain the desired compound(s).

Starting materials of the invention, are either known, commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. Many starting materials may be preparedaccording to known processes and, in particular, can be prepared usingprocesses described in the examples. In synthesizing starting materials,functional groups may be protected with suitable protecting groups whennecessary. Protecting groups, their introduction and removal aredescribed above.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or non-racemicmixtures, scalemic mixtures, single enantiomers, individualdiastereomers and diastereomeric mixtures thereof. Thus, the compoundsmay possess cis- or trans- or E- or Z-double bond isomeric forms. Theoptical isomers can be obtained by resolution of the racemic mixturesaccording to conventional processes, e.g., by formation ofdiastereoisomeric salts, by treatment with an optically active acid orbase. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt.

All such isomeric forms of these compounds are expressly included in thepresent invention. As shown in the examples, many exemplary compounds ofthe present invention have multiple stereocenters, with both cis- andtrans-orientation about the B group-hydroxy substituted carbon-carbonbond. This bond is part of the “Pr” core, as shown in the generalsynthetic schemes. In addition, many compounds of the invention havespecific stereo chemistry about the N—R⁵ bond as well.

The compounds of this invention may also be represented in multipletautomeric forms. The invention expressly includes all tautomeric formsof the compounds described herein.

All crystal forms of the compounds described herein are expresslyincluded in the present invention.

A compound of any of Formulas I-III described herein may be synthesizedaccording to any of the procedures described herein. In the proceduresdescribed herein, the steps may be performed in an alternate order andmay be preceded, or followed, by additional protection/deprotectionsteps as necessary. The procedures may further use appropriate reactionconditions, including inert solvents, additional reagents, such as bases(e.g., LDA, DIEA, pyridine, K₂CO₃, and the like), catalysts, and saltforms of the above. The intermediates may be isolated or carried on insitu, with or without purification. Purification methods are known inthe art and include, for example, crystallization, chromatography(liquid and gas phase, and the like), extraction, distillation,trituration, reverse phase HPLC and the like. Reactions conditions suchas temperature, duration, pressure, and atmosphere (inert gas, ambient)are known in the art and may be adjusted as appropriate for thereaction.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula I-III, the method comprising the step ofreacting a compound 20

wherein i, j, A, B, R³, R⁴ and R⁵ are as defined herein, with a compoundhaving the structure R¹—W—X, wherein R¹ and W are as defined herein andX is a leaving group, to make a compound of claim 1.

As appreciated by one or ordinary skill in the art, compounds of theinvention may be modified by appending appropriate functionalities toenhance selective biological properties. Such modifications are known inthe art and include those which increase biological penetration into agiven biological compartment (e.g., blood, lymphatic system, centralnervous system), increase oral availability, increase solubility toallow administration by injection, alter metabolism and alter rate ofexcretion. By way of example, a compound of the invention may bemodified to incorporate a hydrophobic group or “greasy” moiety in anattempt to enhance the passage of the compound through a hydrophobicmembrane, such as a cell wall.

The pharmacological properties and biological activity of the compoundsof the invention (Formulas I-III) are shown by the following biologicalevaluations.

Biological Evaluation

The following enzyme and cell-based assays were used to characterize theability of compounds of the invention to generally regulate the cleavageof amyloid beta precursor protein, and to inhibit the production ofamyloid beta.

In Vitro Enzymatic BACE FRET (Fluorescence Resonance Energy Transfer)Assay

Assay buffer is 0.05 M acetate, pH 4.2, 10% DMSO final, 100 uM genapol(which is a nonionic detergent, below it's Critical MicelleConcentration). Enzyme (0.2 nM) is pre-incubated for one hour withinhibitors added in 1 uL of DMSO. Then the assay is started by theaddition of FRET substrate (50 nM) and incubated for one hour. The FRETassay is terminated with by addition of Tris buffer, which raises the pHto neutrality, and the fluorescence is determined. The FRET substrate isa peptide with commercially available fluorophore and quencher, onopposite sides of the BACE cleavage site. Proteolytic cleavage of theFRET substrate releases quenching of fluorescence (excitation 488 nm andemission 425 nm).

The compounds of Examples 1-3, 5-10, 12, 14-30, 35, 42-50, 52-54,105-113, 115-138, 140, 142-169, 172-179, 182-190, 192, 194-240, 242-252,254-277, 280-291, 293-294, 296-305, 307-364, 366, 373, 375-388, 390-406,408-418, 420-446, 448-469, 471, 472, 475-477, 480-492, 496-500, 501-503,505-511 and 513-529 exhibited IC₅₀ values of 5 μM or less in the FRETin-vitro enzyme assay.

BACE Cell-Based Assay:

The cell-based assay measures inhibition or reduction of Aβ40 inconditioned medium of test compound treated cells, which express amyloidprecursor protein.

Cells stably expressing Amyloid Precursor Protein (APP) were plated at adensity of 40K cells/well in 96 well plates (Costar). The cells werecultivated for 24 h at 37° C. and 5% CO₂ in DMEM supplemented with 10%FBS. The test compounds were then added to cells in 10-point doseresponse concentrations with the starting concentration being either 100μM or 10 μM. The compounds were diluted from stock solutions in DMSO andthe final DMSO concentration of the test compounds on cells was 0.1%.After 24 hours of incubation with the test compounds the supernatantconditioned media was collected and the Aβ 40 levels were determinedusing a sandwich ELISA. The IC₅₀ of the compound was calculated from thepercent of control or percent inhibition of Aβ 40 as a function of theconcentration of the test compound.

The sandwich ELISA to detect Aβ 40 was performed in 96 well microtiterplates, which were pre-treated with goat anti-rabbit IgG (Pierce). Thecapture and detecting antibody pair that were used to detect Aβ 40 fromcell supernatants were affinity purified pAb40 (Biosource) andbiotinylated 6E10 (Signet Labs Inc.), respectively. The optimalconcentration for the pAb40 antibody was 3 μg/ml in Superblock/TBS(Pierce) that was supplemented with 0.05% Tween 20 (Sigma). Optimalconcentration for the detection antibody 6E10-biotinylated was 0.5 Kg/mlin Superblock/TBS (Pierce) that had been supplemented with 2% normalgoat serum and 2% normal mouse serum.

Cellular supernatants were incubated with the capture antibody for 3 hat 4° C., followed by 3 wash steps in TBS-tween (0.05%). The detectingantibody incubation was for 2 h at 4° C., again followed by the washsteps as described previously. The final readout of the ELISA isTime-Resolved Fluorescence (counts per minute) using Delfia reagentsStreptavidin-Europium and Enhancement solutions (Perkin Elmer) and theVictor 2 multilabel counter (Perkin Elmer).

The compounds of Examples 1-3, 5-10, 12, 14-19, 22-24, 29-30, 32, 43,47-52, 105, 107-108, 110-111, 116-126, 128-138, 140-142, 144, 146-153,158-165, 172-179, 181-189, 191-192, 195-206, 208-215, 218-223, 225-252,254-277, 280-281, 283-291, 293-294, 296-305, 308, 310-313, 318-332,335-344, 348-353, 357-364, 366-375, 378-388, 392-428, 432-436, 438-469,471, 472, 473 and 475-477, 480-529 exhibited activities with IC₅₀ valuesof 5 μM or less in the cell-based assay.

Indications

Accordingly, compounds of the invention are useful for, but not limitedto, the prevention or treatment of beta-secretase related diseases,including Alzheimer's disease. The compounds of the invention have theability to modulate the formation of amyloid beta peptide (A-beta), andreduce the formation and deposition of plaque on the brain. In oneembodiment of the invention, there is provided a method of treating adisorder related to a beta-secretase enzyme in a subject, the methodcomprising administering to the subject an effective dosage amount of acompound of Formulas I, II or III. In another embodiment, there isprovided a method of reducing production of amyloid beta, and ofreducing plaque formation. In yet another embodiment, there is provideda method of treating Alzheimer's disease.

Accordingly, the compounds of the invention would be useful in therapyas CNS agents in treating neurological disorders and related conditions.

Besides being useful for human treatment, these compounds are useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. For example, animalsincluding horses, dogs, and cats may be treated with compounds providedby the invention.

Formulations and Method of Use

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) which may be in need of preventative treatment, such as, forexample, for pain, inflammation and the like. Treatment also encompassesprophylactic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman). Generally, the subject is initially diagnosed by a licensedphysician and/or authorized medical practitioner, and a regimen forprophylactic and/or therapeutic treatment via administration of thecompound(s) or compositions of the invention is suggested, recommendedor prescribed.

The amount of compound(s) which is/are administered and the dosageregimen for treating neurological disorders and beta-secretase mediateddiseases with the compounds and/or compositions of this inventiondepends on a variety of factors, including the age, weight, sex andmedical condition of the subject, the type of disease, the severity ofthe disease, the route and frequency of administration, and theparticular compound employed. Thus, the dosage regimen may vary widely,but can be determined routinely using standard methods. A daily dose ofabout 0.01 to 500 mg/kg, advantageously between about 0.01 and about 50mg/kg, more advantageously about 0.01 and about 30 mg/kg, and even moreadvantageously between about 0.1 and about 10 mg/kg body weight may beappropriate, and should be useful for all methods of use disclosedherein. The daily dose can be administered in one to four doses per day.

While it may be possible to administer a compound of the inventionalone, in the methods described, the compound administered normally willbe present as an active ingredient in a pharmaceutical composition.Thus, in another embodiment of the invention, there is provided apharmaceutical composition comprising a compound of this invention incombination with a pharmaceutically acceptable carrier, which includesdiluents, excipients, adjuvants and the like (collectively referred toherein as “carrier” materials) as described herein, and, if desired,other active ingredients. A pharmaceutical composition of the inventionmay comprise an effective amount of a compound of the invention or aneffective dosage amount of a compound of the invention. An effectivedosage amount of a compound of the invention includes an amount lessthan, equal to or greater than an effective amount of the compound. Forexample, a pharmaceutical composition in which two or more unit dosages,such as in tablets, capsules and the like, are required to administer aneffective amount of the compound, or alternatively, a multi-dosepharmaceutical composition, such as powders, liquids and the like, inwhich an effective amount of the compound is administered byadministering a portion of the composition.

The compound(s) of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The compounds and compositions of the present invention may,for example, be administered orally, mucosally, topically, rectally,pulmonarily such as by inhalation spray, or parentally includingintravascularly, intravenously, intraperitoneally, subcutaneously,intramuscularly intrasternally and infusion techniques, in dosage unitformulations containing conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,advantageously from about 1 to 500 mg, and typically from about 5 to 150mg. A suitable daily dose for a human or other mammal may vary widelydepending on the condition of the patient and other factors, but, onceagain, can be determined using routine methods and practices.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants or “excipients”appropriate to the indicated route of administration. If orallyadministered on a per dose basis, the compounds may be admixed withlactose, sucrose, starch powder, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, to form the final formulation. For example,the active compound(s) and excipient(s) may be tableted or encapsulatedby known and accepted methods for convenient administration. Examples ofsuitable formulations include, without limitation, pills, tablets, softand hard-shell gel capsules, troches, orally-dissolvable forms anddelayed or controlled-release formulations thereof. Particularly,capsule or tablet formulations may contain one or morecontrolled-release agents, such as hydroxypropylmethyl cellulose, as adispersion with the active compound(s).

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, and preferably from about 0.1 to about 10mg/kg.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Accordingly, in yet another embodiment of the present invention, thereis provided a method of manufacturing a medicament, the methodcomprising combining an amount of a compound according to Formulas I, IIor III with a pharmaceutically acceptable carrier to manufacture themedicament.

In yet another embodiment, there is provided a method of manufacturing amedicament for the treatment of Alzheimer's disease, the methodcomprising combining an amount of a compound according to Formulas I, IIor III with a pharmaceutically acceptable carrier to manufacture themedicament.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of beta-secretase,gamma-secretase and/or other reagents known in influence the formationand/or deposition of amyloid beta, otherwise responsible for theformation of plaque on the brain.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I, II and III may also be administered sequentially withknown anti-inflammatory agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with or after administration of the knownanti-inflammatory agent.

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

1. A compound of Formula I:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein A is R¹—C(═O)—, R¹—OC(═O)—, R¹—NHC(═O)—, R¹—S(═O)_(b)— orR¹—NHS(═O)_(b)—, wherein b is 1 or 2; and R¹ is a partially or fullysaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsand optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatomsif bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein said ring system is optionally substitutedindependently with one or more substituents of oxo, R⁷, R⁸, R⁹, NR⁷R⁷,NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)R⁸, OC(O)R⁸,COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷,NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸,NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸,S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸,NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸; B is R²—(CR^(2a)R^(2a))_(h)—,R²—O(CR^(2a)R^(2a))_(h)—, R²—S—(CR^(2a)R^(2a))_(h)— orR²—N(R^(2a))—(CR^(2a)R^(2a))_(h)—, wherein R² is C₁-C₁₀ alkyl, C₁-C₁₀haloalkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl or a partially or fullysaturated or unsaturated 3-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein saidC₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl is optionally substitutedindependently with 5 substituents of R⁹, and said ring system isoptionally substituted independently with 1-5 substituents of oxo, R⁷,R⁸, R⁹, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷,C(O)R⁸, OC(O)R⁸, COOR^(S), C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷,NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸,C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸),OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸,NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸; each R^(2a), independently, is H, OH, NO₂,CN, NH₂, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyl or haloalkyl; and h is 0, 1, 2 or3; i is 1, 2 or 3; j is 0, 1 or 2; each R³, independently, is H,haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of R⁸ or R⁹; R⁴ is H,haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of R⁸ or R⁹; R⁵ is

wherein X¹ is O; each X², independently, is CR¹²R¹²; each of Y¹, Y² andY³, independently, is CR¹²R¹²: m is 1; o is 1; and the fused pyridinering is optionally substituted with 1-5 substituents of R¹², R¹³, R¹⁴ orR¹⁵; R⁷ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸,OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹,C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹; R⁸ is a partially or fully saturated or unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein said ring system is optionally substituted independently with1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹ or a partially orfully saturated or unsaturated 5-6 membered ring of carbon atomsoptionally including 1-3 heteroatoms selected from 0, N, or S, andoptionally substituted independently with 1-5 substituents of R⁹; eachR⁹, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl, benzyl or phenyl; each R¹², independently, is H,halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated orpartially or fully unsaturated 3-8 membered monocyclic or a 6-12membered bicyclic, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl, phenyl or R¹⁴; R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴, SR¹⁴, OR¹⁵; SR¹⁵,C(O)R¹⁴, OC(O)R¹⁴, COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵,NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵),OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵,S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ orNR¹⁵S(O)₂R¹⁵; each R¹⁴, independently, is a saturated or partially orfully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or7-14 membered tricyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S, and wherein said ring system isoptionally substituted independently with 1-5 substituents of R¹⁵; andeach R¹⁵, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, oxo,acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl,isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl,pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl or a partiallyor fully saturated or unsaturated 3-8 membered monocyclic or 6-12membered bicyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, and optionallysubstituted independently with 1-5 substituents of halo, haloalkyl, CN,NO₂, NH₂, OH, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl,propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl,butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl,tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzylor phenyl.
 2. The compound of claim 1 wherein R¹ is

wherein D¹ is CR^(1a′)R^(1a′), NR^(1a′), O or S; D² is NR^(1a′), O or S;E is O or S; each R^(1a), independently, is R⁷, R⁸, R⁹, C(O)R⁷, C(O)R⁸,C(O)NR⁷R⁷, C(S)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂R⁸, orS(O)₂NR⁷R⁸, provided that is not H; each R^(1a′), independently, is R⁷,R⁸, R⁹, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸,S(O)₂NR⁷R⁷, S(O)₂R⁸, or S(O)₂NR⁷R⁸; and each R^(1b), R^(1c) and R^(1d),independently, is R⁷, R⁸, R⁹, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷,COOR⁷, C(O)R⁸, COOR^(S), C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷,NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸,C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸),OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸,NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸.
 3. The compound of claim 1 wherein R² is anoptionally substituted ring system selected from phenyl, naphthyl,pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
 4. Thecompound of claim 1 wherein each R³, independently, is H, haloalkyl, CN,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl; R⁴ is H or C₁₋₁₀-alkyl; andR⁵ is

wherein X¹ is O; each X², independently, is CR¹²R¹²; each of Y¹, Y² andY³, independently, is CR¹²R¹²; m is 1; o is 1; and the fused pyridinering is optionally substituted with 1-5 substituents of R¹², R¹³, R¹⁴ orR¹⁵.
 5. The compound of claim 1 wherein h is 1 or 2; i is 1; j is 0; R¹is

wherein is R⁷, R⁸, R⁹, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, C(O)NR⁷R⁸,C(S)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂R⁸, or S(O)₂NR⁷R⁸, provided that is not H;each R^(1a′), independently, is R⁷, R⁸, R⁹, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷,C(S)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂R⁸, or S(O)₂NR⁷R⁸;each R^(1b), R^(1c) and R^(1d), independently, is R⁷, R⁸, R⁹, NR⁷R⁷,NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, COOR⁷, C(O)R⁸, COOR^(S), C(O)NR⁷R⁷,C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷),OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸,NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷,NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸; Z¹ is anoptionally substituted phenyl, pyridine, pyrimidine, triazine,pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiophene,thiazole, thiadiazole, isothiazole, furan, oxazole, oxadiazole orisoxazole ring; and k is 0, 1, 2 or 3; R² is an optionally substitutedring system selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzisothiazolyl, benzotriazolyl and benzimidazolyl;each R³, independently, is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenylor C₂₋₁₀-alkynyl; R⁴ is H, CN or C₁₋₁₀-alkyl; R⁵ is

wherein X¹ is O; each X², independently, is CR¹²R¹²; each of Y¹, Y² andY³, independently, is CR¹²R¹²: m is 1; o is 1; and the fused pyridinering is optionally substituted with 1-5 substituents of R¹², R¹³, R¹⁴ orR¹⁵; each R⁷, independently, is H, C₁₋₁₀-alkyl or C₂₋₁₀-alkenyl, each ofthe C₁₋₁₀-alkyl, or C₂₋₁₀-alkenyl optionally substituted with 1-3substituents of R⁹; R⁸ is a ring system selected from phenyl, pyridyl,pyrimidinyl, triazinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl,benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl,isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl,isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl,1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl,cyclohexyl and cycloheptyl, said ring system optionally substitutedindependently with 1-3 substituents of R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from O, N, orS, and optionally substituted independently with 1-5 substituents of R⁹;each R⁹, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkenyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl, or a ring system selected from phenyl,pyridyl, pyrimidinyl, triazinyl, thiophenyl, furyl, tetrahydrofuranyl,pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl,tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl,isothiazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl and cycloheptyl, whereineach of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,tert-butyl, cyclobutyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl, benzyl or phenyl; and each R¹², independently, is H,halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkenyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated orpartially or fully unsaturated 3-8 membered monocyclic or a 6-12membered bicyclic, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkenyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl.
 6. The compound of claim 1 of Formula I:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,wherein A is R¹—C(═O)—, R¹—OC(═O)—, R¹—NHC(═O)—, R¹—S(═O)_(b)— orR¹—NHS(═O)_(b)—, wherein b is 1 or 2; and R¹ is a partially or fullysaturated 4-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsand optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatomsif bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, wherein said ring system is optionally substitutedindependently with one or more substituents of oxo, R⁷, R⁸, R⁹, NR⁷R⁷,NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)R⁸, OC(O)R⁸,COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷,NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸,NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸, NR⁷(COOR⁸), OC(O)NR⁷R⁸,S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁸,NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸; B is R²—O—(CR^(2a)R^(2a))_(h)—,R²—S—(CR^(2a)R^(2a))_(h)—, or R²—N(R^(2a))—(CR^(2a)R^(2a))_(h)—, whereinR² is C₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl or a partially orfully saturated or unsaturated 5-8 membered monocyclic, 6-12 memberedbicyclic, or 7-14 membered tricyclic ring system, said ring systemformed of carbon atoms optionally including 1-3 heteroatoms ifmonocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms iftricyclic, said heteroatoms selected from O, N, or S, wherein saidC₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl is optionally substitutedindependently with one or more substituents of R⁹, and said ring systemis optionally substituted independently with one or more substituents ofoxo, R⁷, R⁸, R⁹, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, OC(O)R⁷,COOR⁷, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)NR⁷R⁷, C(S)NR⁷R⁷, NR⁷C(O)R⁷,NR⁷C(S)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷C(S)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷,C(O)NR⁷R⁸, C(S)NR⁷R⁸, NR⁷C(O)R⁸, NR⁷C(S)R⁸, NR⁷C(O)NR⁷R⁸, NR⁷C(S)NR⁷R⁸,NR⁷(COOR⁸), OC(O)NR⁷R⁸, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷, NR⁷S(O)₂R⁷, S(O)₂R⁸,S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸ or NR⁷S(O)₂R⁸; each R^(2a), independently, isH, OH, NO₂, CN, NH₂, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyl or haloalkyl; and h is1; i is 1; j is 0; each R³, independently, is H, haloalkyl, CN,C₂₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with 1-5 substituents of R⁸ or R⁹; R⁴ is H, haloalkyl, CN,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl orC₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionallycomprising 1-4 heteroatoms selected from N, O and S and optionallysubstituted with 1-5 substituents of R⁸ or R⁹; R⁵ is

wherein X¹ is O; each X², independently, is CR¹²R¹²; each of Y¹, Y² andY³, independently, is CR¹²R¹²; m is 1; o is 1; and the fused pyridinering is optionally substituted with 1-5 substituents of R¹², R¹³, R¹⁴ orR¹⁵; each R⁷, independently, is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of NR⁸R⁹,NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹,COOR^(S), C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹,NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸,S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹,NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹; R⁸ is a partially or fully saturatedor unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S, and wherein said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹; SR⁹, C(O)R⁹or a partially or fully saturated or unsaturated 5-6 membered ring ofcarbon atoms optionally including 1-3 heteroatoms selected from 0, N, orS, and optionally substituted independently with 1-5 substituents of R⁹;each R⁹, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl,hexyl, cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl, benzyl or phenyl; each R¹², independently, is H,halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated orpartially or fully unsaturated 3-8 membered monocyclic or a 6-12membered bicyclic, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl, phenyl or R¹⁴; R¹³ is NR¹⁴R¹⁵, NR¹⁵R¹⁵, OR¹⁴, SR¹⁴, OR¹⁵; SR¹⁵,C(O)R¹⁴, OC(O)R¹⁴, COOR¹⁴, C(O)R¹⁵, OC(O)R¹⁵, COOR¹⁵, C(O)NR¹⁴R¹⁵,C(O)NR¹⁵R¹⁵, NR¹⁴C(O)R¹⁴, NR¹⁵C(O)R¹⁴, NR¹⁴C(O)R¹⁵, NR¹⁵C(O)R¹⁵,NR¹⁵C(O)NR¹⁴R¹⁵, NR¹⁵C(O)NR¹⁵R¹⁵, NR¹⁵(COOR¹⁴), NR¹⁵(COOR¹⁵),OC(O)NR¹⁴R¹⁵, OC(O)NR¹⁵R¹⁵, S(O)₂R¹⁴, S(O)₂R¹⁵, S(O)₂NR¹⁴R¹⁵,S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂NR¹⁴R¹⁵, NR¹⁵S(O)₂NR¹⁵R¹⁵, NR¹⁴S(O)₂R¹⁴ orNR¹⁵S(O)₂R¹⁵; each R¹⁴, independently, is a saturated or partially orfully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or7-14 membered tricyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from O, N, or S, and wherein said ring system isoptionally substituted independently with 1-5 substituents of R¹⁵; eachR¹⁵, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, oxo,acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl,isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl,pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl or a partiallyor fully saturated or unsaturated 3-8 membered monocyclic or 6-12membered bicyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, and optionallysubstituted independently with 1-5 substituents of halo, haloalkyl, CN,NO₂, NH₂, OH, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl,propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl,butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl,tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzylor phenyl; and each R¹⁶, independently, is haloalkyl, methyl, methoxyl,ethyl, ethoxyl, alkoxy-alkyl, alkylamino-alkyl, dialkylamino-alkyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, butyl, isobutyl,sec-butyl or tert-butyl.
 7. The compound of claim 1, or apharmaceutically acceptable salt thereof, selected from:(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)tetrahydro-2-furancarboxamide;(2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)tetrahydro-2-furancarboxamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)tetrahydro-3-furancarboxamide;(2S,2R)—N-((1S,2R)-3-((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)tetrahydro-2-furancarboxamide;1′-cyclopentyl-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4′S)-6′-((2S)-tetrahydro-2-furanylmethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2′-oxo-1′,2′-dihydro-2,3′-bipyridine-5′-carboxamide;1-cyclopentyl-N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-6-oxo-5-(tetrahydro-2H-pyran-2-yl)-1,6-dihydro-3-pyridinecarboxamide;(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-5-oxotetrahydro-2-furancarboxamide;N-((2S,3R)-3-hydroxy-4-((S)-6-neopentyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-tetrahydrofuran-2-carboxamide;1-Cyclopentyl-6-oxo-5-(pyridin-2-yl)-N-((3S,4R)-1,1,1-trifluoro-4-hydroxy-5-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)pentan-3-yl)-1,6-dihydropyridine-3-carboxamide;1-cyclopentyl-5-(2-fluorophenyl)-N-((2S,3R)-3-hydroxy-4-((S)-6-neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide;1-cyclopentyl-N-((2S,3R)-3-hydroxy-4-((S)-6-neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-5-(thiazol-2-yl)-1,6-dihydropyridine-3-carboxamide;1-cyclopentyl-N-((2S,3R)-3-hydroxy-4-((S)-6-neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-5-(pyrazin-2-yl)-1,6-dihydropyridine-3-carboxamide;1-cyclopentyl-N-((2S,3S)-3-hydroxy-4-((S)-6-neopentyl-3,4-dihydro-2,2-spirocyclobutyl-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide;1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide;1-cyclopentyl-N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6-(trifluoromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(2-oxopyrrolidin-1-yl)-1,6-dihydropyridine-3-carboxamide;1-cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-5-(pyridin-2-yl)-1,6-dihydropyridine-3-carboxamide;N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-6-oxo-1-((R)-tetrahydrofuran-3-yl)-1,6-dihydropyridine-3-carboxamide;(S)—N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-oxo-tetrahydrofuran-2-carboxamide;and(S)—N-((2S,3R)-1-(3-cyanophenyl)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxybutan-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxamide.8. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound according to claim
 1. 9. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound according to claim
 7. 10. A method of making a compound ofclaim 1, the method comprising the step of reacting a compound 20

wherein i, j, A, B, R³, R⁴ and R⁵ are as defined in claim 1, with acompound having the structure A-X, wherein A is as defined in claim 1and X is a leaving group, to make a compound of claim 1.